Device with needle penetrable and laser resealable portion and related method

ABSTRACT

A device and method are provided for needle penetrating and filling a chamber with a predetermined substance, and laser resealing a resulting needle hole in the device. A needle penetrable and laser resealable portion of the device is pierceable with a needle to form a needle aperture therethrough to fill the chamber through the needle, and is laser resealable to hermetically seal the needle aperture by applying laser radiation at a predetermined wavelength and power thereto. The needle penetrable and laser resealable portion defines a predetermined wall thickness in an axial direction thereof, and includes a thermoplastic that substantially prevents the formation of particles released into the chamber from the needle penetrable and laser resealable portion during penetration by and withdrawal of the needle. The thermoplastic includes a predetermined amount of pigment that allows the thermoplastic to substantially absorb laser radiation at the predetermined wavelength, substantially prevent the passage of radiation through the predetermined wall thickness thereof, and hermetically seal a needle aperture formed in the needle penetration region thereof in a predetermined time period.

CROSS-REFERENCE TO RELATED APPLICATIONS

This patent application is a continuation of U.S. patent applicationSer. No. 10/766,172, filed Jan. 28, 2004, entitled “Medicament VialHaving a Heat-Sealable Cap, and Apparatus and Method for Filling theVial”, now U.S. Pat. No. 7,032,631, which is a continuation-in-part ofU.S. patent application Ser. No. 10/694,364, filed Oct. 27, 2003,entitled “Medicament Vial Having A Heat-Sealable Cap, And Apparatus andMethod For Filling The Vial”, now U.S. Pat. No. 6,805,170, which is acontinuation of similarly titled U.S. patent application Ser. No.10/393,966, filed Mar. 21, 2003, now U.S. Pat. No. 6,684,916, which is adivisional of similarly titled U.S. patent application Ser. No.09/781,846, filed Feb. 12, 2001, now U.S. Pat. No. 6,604,561, which, inturn, claims the benefit of similarly titled U.S. ProvisionalApplication Ser. No. 60/182,139, filed Feb. 11, 2000. Further, parentapplication Ser. No. 10/766,172 claims priority on similarly titled U.S.Provisional Patent Application No. 60/442,526, filed Jan. 28, 2003, andsimilarly titled U.S. Provisional Patent Application No. 60/484,204,filed Jun. 30, 2003. The foregoing applications and patents are herebyexpressly incorporated by reference as part of the present disclosure.

FIELD OF THE INVENTION

The present invention relates to heat-sealable caps or stoppers forvials or other containers for storing medicaments or other substancesfor use where a sterile medicament or other substance must be maintainedfollowing temporary introduction of a needle or syringe through the capor stopper, and to apparatus and methods for filling such vials or othercontainers.

BACKGROUND OF THE INVENTION

A typical medicament dispenser includes a body defining a storagechamber, a fill opening in fluid communication with the body, and astopper or cap for sealing the fill opening after filling the storagechamber to hermetically seal the medicament within the dispenser. Inorder to fill such prior art dispensers with a sterile fluid or othersubstance, such as a medicament, it is typically necessary to sterilizethe unassembled components of the dispenser, such as by autoclaving thecomponents and/or exposing the components to gamma radiation. Thesterilized components then must be filled and assembled in an asepticisolator of a sterile filling machine. In some cases, the sterilizedcomponents are contained within multiple sealed bags or other sterileenclosures for transportation to the sterile filling machine. In othercases, the sterilization equipment is located at the entry to thesterile filling machine. In a filling machine of this type, everycomponent is transferred sterile into the isolator, the storage chamberof the vial is filled with the fluid or other substance, the sterilizedstopper is assembled to the vial to plug the fill opening andhermetically seal the fluid or other substance in the vial, and then acrimping ring is assembled to the vial to secure the stopper thereto.

One of the drawbacks associated with such prior art dispensers, andprocesses and equipment for filling such dispensers, is that the fillingprocess is time consuming, and the processes and equipment areexpensive. Further, the relatively complex nature of the fillingprocesses and equipment can lead to more defectively filled dispensersthan otherwise desired. For example, typically there are at least asmany sources of failure as there are components. In many cases, thereare complex assembly machines for assembling the vials or otherdispensers that are located within the aseptic area of the fillingmachine that must be maintained sterile. This type of machinery can be asignificant source of unwanted particles. Further, such isolators arerequired to maintain sterile air within the barrier enclosure. In closedbarrier systems, convection flow is inevitable and thus laminar flow, orsubstantially laminar flow, cannot be achieved. When operation of anisolator is stopped, a media fill test may have to be performed whichcan last for several, if not many days, and can lead to repeatedinterruptions and significant reductions in production output for thepharmaceutical or other product manufacturer that is using theequipment. In order to address such production issues,government-imposed regulations are becoming increasingly sophisticatedand are further increasing the cost of already-expensive isolators andlike filling equipment. On the other hand, governmental price controlsfor injectables and vaccines, including, for example, preventativemedicines, discourage such major financial investments. Accordingly,there is a concern that fewer companies will be able to afford suchincreasing levels of investment in sterile filling machines, thusfurther reducing competition in the injectable and vaccine marketplaces.

In order to address these and other concerns, the present inventor hasdetermined that it would be desirable to manufacture and fill vials byfirst assembling the cap to the vial, sterilizing the assembled cap andvial, such as by irradiation, and then filling the assembled vial byinserting a needle or like injection member through the cap andintroducing the medicament through the needle into the sterilized vial.One of the drawbacks associated with this approach, however, is thatwhen the needle or like injection member is inserted through the cap andthen withdrawn, it leaves a tiny hole in the cap. The material of thecap is resilient in order to reduce the diameter of the hole, andtherefore the hole is usually small enough to keep the medicament fromleaking out. However, the hole typically is not small enough to preventair or other gases from passing through the hole and into the vial, andtherefore such holes can allow the medicament to become contaminated orspoiled.

It has been a practice in the pharmaceutical fields to add preservativesto medicaments, such as vaccines, in order to prevent spoilage of themedicaments upon exposure to air or other possible contaminants. Certainpreservatives, however, have been determined to cause undesirableeffects on patients. Consequently, many medicaments, including vaccines,are preservative free. These preservative-free medicaments, andparticularly preservative-free vaccines, are subject to contaminationand/or spoilage if contained within a vial wherein the cap has a needlehole as described above.

Accordingly, it is an object of the present invention to overcome one ormore of the above-described drawbacks and disadvantages of the priorart.

SUMMARY OF THE INVENTION

In accordance with a first aspect, the present invention is directed toa device including a needle penetrable and laser resealable portion thatis pierceable with a needle to form a needle aperture therethrough tofill a chamber of the device with a predetermined substance through theneedle, and is laser resealable to hermetically seal the needle apertureby applying laser radiation at a predetermined wavelength and powerthereto. The needle penetrable and laser resealable portion defines apredetermined wall thickness in an axial direction thereof, and includesa thermoplastic that substantially prevents the formation of particlesreleased into the chamber from the needle penetrable and laserresealable portion during penetration by and withdrawal of the needle.The thermoplastic includes a predetermined amount of pigment that allowsthe thermoplastic to substantially absorb laser radiation at thepredetermined wavelength, substantially prevent the passage of radiationthrough the predetermined wall thickness thereof, and hermetically seala needle aperture formed in the needle penetration region thereof in apredetermined time period of less than approximately 2 seconds.

In one embodiment of the present invention, the thermoplastic includesan olefin within the range of about 3% to about 20% by weight, a styreneblock copolymer within the range of about 80% to about 97% by weight,and a lubricant. In one embodiment of the present invention, thethermoplastic includes (i) a first polymeric material in an amountwithin the range of about 80% to about 97% by weight and defining afirst elongation, (ii) a second polymeric material in an amount withinthe range of about 3% to about 20% by weight and defining a secondelongation that is less than the first elongation of the first material,and (iii) a lubricant in an amount that reduces friction forces at aninterface of the needle and body. In one such embodiment, the firstmaterial is a styrene block copolymer and the second material is anolefin. In one embodiment of the present invention, the predeterminedamount of pigment is within the range of about 0.3% to about 0.6% byweight.

In accordance with another aspect of the present invention, the needlepenetrable and laser resealable portion includes (i) an underlyingportion formed of a first material compatible with the predeterminedsubstance and defining a substance-exposed surface exposed to thepredetermined substance within the device; and (ii) a resealable portionoverlying the underlying portion, wherein the resealable portion ispenetrable by the needle for introducing the predetermined substancethrough the stopper and into the device. In one such embodiment, thepenetrable region of the underlying portion is substantially infusiblein response to the application of radiation from the laser source, andthe penetrable region of the resealable portion is fusible in responseto the application of radiation from the laser source to form agas-tight seal between the resealable portion and the predeterminedsubstance in the device after removing the needle therefrom. In oneembodiment, the device is a vial. In another embodiment, the device is asyringe.

In accordance with another aspect, the present invention is directed tothe device in combination with a needle for penetrating the needlepenetrable and laser resealable portion. The needle includes anon-coring, conically-pointed tip defining an included angle within therange of about 15 degrees to about 25 degrees.

In accordance with another aspect, the present invention is directed toa device including a needle penetrable and laser resealable portion thatis pierceable with a needle to form a needle aperture therethrough tofill a chamber of the device with a predetermined substance through theneedle, and is laser resealable to hermetically seal the needle apertureby applying laser radiation at a predetermined wavelength and powerthereto. The needle penetrable and laser resealable portion includes athermoplastic and defines a predetermined wall thickness in an axialdirection thereof. The needle penetrable and laser resealable portionfurther includes (i) first means for substantially preventing theformation of particles released into the chamber from the stopper uponpenetrating the stopper with the needle and withdrawing the needle fromthe stopper, and (ii) second means for allowing the thermoplastic tosubstantially absorb laser radiation at the predetermined wavelength andsubstantially prevent the passage of radiation through the predeterminedwall thickness thereof, and hermetically seal a needle aperture formedin the needle penetration region thereof in a predetermined time periodof less than approximately 2 seconds.

In one embodiment of the present invention, the first means is definedby the thermoplastic including a styrene block copolymer, an olefin, anda lubricant. In one such embodiment, the thermoplastic includes anolefin within the range of about 3% to about 20% by weight, and astyrene block copolymer within the range of about 80% to about 97% byweight.

In one embodiment of the present invention, the first means is definedby the thermoplastic including (i) a first polymeric material in anamount within the range of about 80% to about 97% by weight and defininga first elongation, (ii) a second polymeric material in an amount withinthe range of about 3% to about 20% by weight and defining a secondelongation that is less than the first elongation of the first material,and (iii) a lubricant in an amount that reduces friction forces at aninterface of the needle and body.

In accordance with another aspect, the present invention is directed toa method of providing and filling a device with a predeterminedsubstance. The method comprises the following steps: (i) providing aneedle penetrable and laser resealable portion including a thermoplasticthat is pierceable with a needle to form a needle aperture therethrough,and is laser resealable to hermetically seal the needle aperture byapplying laser radiation at a predetermined wavelength and powerthereto, wherein the needle penetrable and laser resealable portiondefines a predetermined wall thickness in an axial direction thereof;(ii) providing the thermoplastic with a predetermined amount of pigmentthat allows the needle penetrable and laser resealable portion tosubstantially absorb laser radiation at the predetermined wavelength andsubstantially prevent the passage of radiation through the predeterminedwall thickness; (iii) connecting the needle penetrable and laserresealable portion to a device defining a chamber; (iv) providing aneedle defining a non-coring, conically-pointed tip and at least oneflow aperture located adjacent to the tip and connectable in fluidcommunication with a source of the predetermined substance; (v)configuring at least one of the needle penetrable and laser resealableportion and needle to substantially prevent the formation of particlesreleased into the chamber from the thermoplastic upon penetrating samewith the needle and withdrawing the needle therefrom; (vi) penetratingthe needle penetrable and laser resealable portion with theconically-pointed tip of the needle such that the flow aperture of theneedle is in fluid communication with the chamber of the device, andsubstantially preventing the formation of particles released intochamber from the thermoplastic during penetration by the needle; (vii)introducing the predetermined substance through the needle and into thechamber of the device, withdrawing the needle from the needle penetrableand laser resealable portion, and substantially preventing the formationof particles released into the chamber from the thermoplastic duringwithdrawal of the needle; and (viii) transmitting laser radiation at thepredetermined wavelength and power onto the needle penetrated region ofthe needle penetrable and laser resealable portion, and hermeticallysealing the needle aperture formed in the needle penetrable and laserresealable portion and the predetermined substance within the chamber.

In one embodiment of the present invention, the step of configuring atleast one of the needle penetrable and laser resealable portion andneedle to substantially prevent the formation of particles released intothe chamber includes providing a thermoplastic including a styrene blockcopolymer and an olefin, and providing a lubricant at an interface ofthe needle and needle penetrable and laser resealable portion. In onesuch embodiment, the method further comprises providing a thermoplasticincluding an olefin within the range of about 3% to about 20% by weight,and a styrene block copolymer within the range of about 80% to about 97%by weight. In one such embodiment, the step of providing a lubricantincludes providing within the thermoplastic a predetermined amount oflubricant that reduces friction forces at the interface of the needleand thermoplastic. In one such embodiment, the step of providing alubricant includes providing a lubricant selected from the groupincluding silicone, mineral oil and silicone oil.

In one embodiment of the present invention, the step of configuring atleast one of the needle penetrable and laser resealable portion andneedle to substantially prevent the formation of particles released intothe chamber includes providing a low-friction coating on the needle. Inone such embodiment, the low-friction coating is selected from the groupincluding tungsten carbide and titanium.

In one embodiment of the present invention, the step of configuring atleast one of the needle penetrable and laser resealable portion andneedle to substantially prevent the formation of particles released intothe chamber includes providing a thermoplastic including (i) a firstpolymeric material in an amount within the range of about 80% to about97% by weight and defining a first elongation, (ii) a second polymericmaterial in an amount within the range of about 3% to about 20% byweight and defining a second elongation that is less than the firstelongation of the first material, and (iii) a lubricant in an amountthat reduces friction forces at an interface of the needle and needlepenetrable and laser resealable portion.

In accordance with another aspect, the method further comprises thesteps of molding the needle penetrable and laser resealable portion anddevice; and prior to allowing the needle penetrable and laser resealableportion and device to cool to an ambient temperature, assembling theneedle penetrable and laser resealable portion and device and forming asealed, sterile chamber therebetween.

The method preferably further comprises the step of sterilizing thesealed, empty needle penetrable and laser resealable portion and deviceassembly prior to the step of needle penetrating the needle penetrableand laser resealable portion. In some such embodiments, the sterilizingstep is selected from the group including (i) applying gamma radiation,(ii) applying e-beam radiation, and (iii) applying laser radiation, tothe sealed, empty needle penetrable and laser resealable portion anddevice assembly.

In accordance with another aspect of the present invention, the step ofproviding a needle penetrable and laser resealable portion includesproviding a needle penetrable and laser resealable portion defining anunderlying portion formed of a first material compatible with thepredetermined substance and defining a substance-exposed surface exposedto the predetermined substance within the device, and a resealableportion overlying the underlying portion. The resealable portion andunderlying portion are penetrable by the needle for introducing thepredetermined substance through the needle penetrable and laserresealable portion and into the chamber. In one such embodiment, thestep of providing a needle penetrable and laser resealable portionfurther includes providing a penetrable region of the underlying portionthat is substantially infusible in response to the application ofthermal energy from the laser source, and providing a penetrable regionof the resealable portion that is fusible in response to the applicationof thermal energy from the laser source to form a gas-tight seal betweenthe resealable portion and the predetermined substance in the deviceupon removing the needle therefrom.

In accordance with another aspect of the present invention, the step ofintroducing the predetermined substance through the needle and into thechamber of the device includes introducing the predetermined substancethrough a first fluid passageway of the needle, and allowing fluid toflow out of the chamber through a second fluid passageway uponintroducing predetermined substance from the first fluid passageway intothe chamber.

One advantage of the apparatus and method of the present invention, isthat the caps and locking members are secured to the vials prior tofilling, thus enhancing the ability to maintain sterile conditionsthroughout the filling process and avoiding the need to assemble thevials in a sterile environment. As a result, the apparatus and method ofthe present invention significantly reduce processing time and cost incomparison to prior art vials and filling systems, and moreover,significantly increase the assurance of sterility throughout theassembly and filling processes.

Other advantages of the present invention will become readily apparentin view of the following detailed description and accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a somewhat schematic, partly-exploded, cross-sectional view ofa prior art end cap for a medicament vial.

FIG. 2 is a cross-sectional, partly-exploded view of a resealable capembodying the present invention.

FIG. 3 is a cross-sectional, partly-exploded view of the resealable capof FIG. 2 shown with an injection needle or syringe inserted through theend cap for introducing medicament into the vial, and a venting needleor syringe inserted through the end cap for venting the vial duringfilling of the medicament.

FIG. 4 is a cross-sectional view of another embodiment of the resealablecap and vial of the present invention.

FIG. 5 is a cross-sectional view of the crimpable locking member of FIG.4 for securing the resealable cap to the vial.

FIG. 6 is a cross-sectional view of the base portion of the resealablecap of FIG. 4 made of a material compatible with the predeterminedmedicament to be sealed within the vial, such as vulcanized rubber.

FIG. 7 is a cross-sectional view of the resealable portion of the cap ofFIG. 4 formed of a material that is fusible in response to theapplication of thermal energy thereto in order to hermetically seal thecap after inserting and removing a filling needle or like instrumenttherethrough.

FIG. 8 is an enlarged, partial, cross-sectional view of the resealableportion of FIG. 7 and showing the penetrable portion thereof forreceiving a needle or like instrument therethrough.

FIGS. 9A through 9C are somewhat schematic, cross-sectional, sequentialviews illustrating an apparatus and method of the present invention forsterilizing the resealable portion of the cap by direct heatcauterization prior to introducing the filling needle or like instrumenttherethrough.

FIG. 10 is a somewhat schematic, partial cross-sectional view of anapparatus embodying the present invention for sterilizing the resealableportion of the cap by laser cauterization prior to introducing thefilling needle or like instrument therethrough.

FIG. 11 is a somewhat schematic, partial cross-sectional view of anapparatus embodying the present invention for needle filling theassembled cap, vial and locking member with a predetermined medicament.

FIGS. 12A through 12D are somewhat schematic, cross-sectional,sequential views illustrating the apparatus and method of the presentinvention for hermetically sealing the penetrated region of theresealable portion of the cap by direct heat sealing after withdrawingthe filling needle therefrom.

FIGS. 13A through 13C are somewhat schematic, cross-sectional,sequential views illustrating the apparatus and method of the presentinvention for hermetically sealing the penetrated region of theresealable portion of the cap by laser sealing after withdrawing thefilling needle therefrom.

FIG. 14 is a cross-sectional view of another embodiment of a vialassembly including a resealable stopper of the present invention.

FIG. 15 is a cross-sectional view of another embodiment of a vialassembly including a resealable stopper of the present invention.

FIG. 16 is representation of a conventional facility and method forsterile filling of medicaments intended for intravenous injection orother sterile substances.

FIG. 17 is representation of a facility and method for sterile fillingof medicaments or other sterile substances, in accordance with anotheraspect of the present invention.

FIG. 18 is a perspective view of a filling machine in accordance withanother aspect of the present invention.

FIG. 19 is a perspective view of the filling machine of FIG. 18including a pair of gloves mounted to the glove ports for allowing auser to access the interior of the filling machine, and a bag defining asterile enclosure mounted to the sterile transfer port for transferringarticles into and out of the sterile or aseptic interior of the fillingmachine.

FIG. 20 is a perspective, somewhat schematic view of the filling machineof FIGS. 18 and 19.

FIG. 21 is a somewhat schematic, partial, cross-sectional view of thefilling machine of FIGS. 18-20 with some parts removed for clarity.

FIG. 22 is a perspective view of the barrier of the filling machine ofFIGS. 18-20.

FIG. 23 is a side elevational view of the filling machine of FIGS. 18-20with some parts removed for clarity.

FIGS. 24, 25, 26A and 26B are enlarged perspective views of the infeedunit and the fill unit of the filling machine of FIGS. 18-20, shownwithout the barrier portion.

FIG. 27 is a further enlarged, partial, perspective view of the infeedunit of FIG. 26.

FIG. 28 is a further enlarged, partial, perspective view of a portion ofthe infeed unit of FIG. 27.

FIGS. 28A-28I are partial, perspective views of an alternativeembodiment of the infeed unit of the filling machine of FIGS. 18-20showing progressively the infeeding of a tray of vials into the infeedunit and, in turn, onto the turntable of the filling unit of the sterilefilling machine.

FIG. 29 illustrates another embodiment of a tray arrangement that may beused to load vials or other containers into the infeed unit.

FIGS. 30A-30F are enlarged perspective views of the filling unit of thefilling machine of FIGS. 18-20 including one embodiment of a lasersealing and IR sensing manifold used therein.

FIGS. 31A-31H are enlarged perspective views of the needle manifold ofthe filling unit of FIGS. 30A-30F showing progressively the movement ofthe needle manifold between a non-actuated position spaced above thevials, and an actuated position with the needles penetrating therespective needle penetration regions of the resealable stoppers of thevials located within the filling station for filling the interiorchambers of the vials with a medicament or other substance.

FIG. 32 is a further enlarged perspective view of an example of a needlethat may be mounted in the needle manifold of FIGS. 31A-31H.

FIGS. 33A-33B are views of one embodiment of the needle of FIG. 32.

FIG. 34 includes a plurality of cross-sectional views of a pencil pointtype needle that may be mounted in the needle manifold of FIGS. 31A-31H.

FIG. 35 includes a plurality of cross-sectional views of another needlethat may be mounted in the needle manifold of FIGS. 31A-31H.

FIG. 36 is an enlarged elevational view of the laser sealing and IRsense manifold of FIGS. 30A-30F.

FIGS. 37A-37D are perspective views of one embodiment of the laser opticand IR sensor assembly used in the laser sealing and IR sense manifoldof FIGS. 30A-30F.

FIG. 38 is an elevational view of a portion of the fill assembly of thefilling machine of FIGS. 18-20 including the first star wheel, theturntable, and the second star wheel.

FIGS. 39A-39C show side elevational views of sequential steps employedto insert a tray of containers into the infeed unit of the sterilefilling machine of FIGS. 18-20.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

As shown in FIG. 1, a prior art cap for a medicament vial is generallydesignated by the reference numeral 10. The cap 10 includes a vulcanizedrubber base 12, which is slidably received within the open end of a vial14. The vial 14 is made of glass or like material, and it defines achamber 16 for receiving medicament. An aluminum locking ring 18surrounds the periphery of the cap 12 and vial 14, and it is crimped inplace to lockably connect and seal the cap to the vial.

In operation, a hypodermic needle (not shown) is inserted through thevulcanized rubber base in order to deposit medicament within the chamber16. Once the medicament has been deposited, the needle is withdrawn fromthe cap 10. Although the hole resulting from insertion of the needlewill shrink somewhat from its maximum diameter due to the resiliency ofthe vulcanized rubber, the resultant hole is typically still largeenough to pass gas or vapor and thereby compromise any preservative-freemedicament contained within the chamber 16.

Turning to FIG. 2, a heat-resealable cap or stopper embodying thepresent invention is indicated generally by the reference numeral 110.The cap 110 includes a resilient base 112 made of vulcanized rubber orlike material which is known to those of ordinary skill in the pertinentart, and acceptable for use in the manufacture of end caps or theportions thereof placed in contact with, or otherwise exposed tomedicaments, such as vaccines. The base 112 defines a lower peripheralwall 115 shaped and dimensioned to be slidably received within the openend of a vial 114. The vial 114 is made of glass or like material, andit defines a chamber 116 for receiving medicament. The base 112 of thecap 110 further defines an upper peripheral wall 117 also shaped anddimensioned to be slidably received within the open end of the vial 114,and a peripheral sealing flange 118 projecting outwardly from the upperend of the peripheral wall 117. The vial 114 is made of glass or othersuitable material, and defines at its open end a peripheral flange 120.As shown partly exploded in FIGS. 2 and 3, the peripheral flange 118 ofthe base 112 sealingly engages the peripheral flange 120 of the vial 114to seal the interface between the cap and vial. The base 112 furtherdefines an upper recess 122 formed within the upper peripheral wall 117,and an annular rim 124 projecting inwardly from the upper end of theperipheral wall.

A resealable member 126 is fixedly received within the upper recess 122of the base 112 to form the assembled cap 110. The resealable member 126defines an upper peripheral flange 128, an annular recessed portion orrecess 130, and a base 132 located on the opposite side of the annularrecess 130 relative to the flange, and projecting outwardly from therecess. As can be seen in FIGS. 2 and 3, the annular recess 130 and base132 of the resealable member 126 are dimensioned and shapedcomplementary to (or define the mirror image of) the interior surfacesof the upper recess 122 and annular rim 124 of the base 112.Accordingly, the resealable member 126 is pressed, snapped or otherwisereceived within the upper recess 122 such that the annular rim 124 isreceived within the annular recess 130 to thereby fixedly secure theresealable member within the base.

In one embodiment of the present invention, the resealable member 126 ismade of a resilient polymeric material, such as a blend of the polymericmaterial sold by Kraton Polymers and GLS Corporation under theregistered trademark KRATON® and a low-density polyethylene, such as thepolyethylene sold by Dow Chemical Co. under the trademarks ENGAGE™ orEXACT™, or can be made of other resilient polymeric materials asdescribed in connection with alternative embodiments of the resealablestopper below. An important feature of the resealable member 126 is thatit be resealable to form a gas-tight seal after inserting a needle,syringe or like injection member through the resealable member.Preferably, the resealable member can be sealed by heating the areapunctured by the needle in a manner known to those skilled in thepertinent art and described further below. One advantage of the blendedpolymer described above is that it is known to minimize the degree towhich the medicament can be absorbed into the polymer in comparison toKRATON® itself.

An aluminum locking or crimping ring 134 defining an upper peripheralflange 136 and a lower peripheral flange 138 is mounted over the end cap110 and vial 114. The locking ring 134 is of a type known to those ofordinary skill in the pertinent art for fixedly securing end caps tovials, and may take the shape or form of any of numerous differentlocking rings which are currently or later become known for performingthe functions of the locking ring described herein. The upper and lowerflanges 136 and 138, respectively, of the locking ring are crimped orotherwise pressed against the adjacent surfaces of the cap and vial topress the sealing flanges of the cap against the vial and therebymaintain a fluid-tight and/or gas-tight seal between the cap and vial.

As shown in FIG. 3, the heat-resealable cap 110 is shown with ahypodermic or other type of needle 140 inserted through the resealablemember 126 and the resilient base 112 in order to dispense medicamentinto the chamber 116 of the vial. A venting needle 142 is likewiseinserted through the resealable member 126 and the resilient base 112 inorder to allow gas to escape from the vial 114 as the medicament isdeposited into the vial.

In operation, the resealable member 126 is inserted into the base 112,and the assembled end cap 110 is slidably inserted into the open end ofthe vial 114. The locking ring 134 is then crimped in place to lock thecap 110 to the vial and maintain the gas-tight seal at the interface ofthe cap and vial. The assembled cap 110 and vial 114 preferably are thensterilized, such as by exposing the assembly to beta and/or gammaradiation in a manner known to those of ordinary skill in the pertinentart. The medicament-dispensing needle 140 is then inserted through theresealable member 126 and the resilient base 112 until the free end ofthe needle is received into the chamber 116 of the vial to, in turn,dispense medicament into the chamber. The venting needle 142 is likewiseinserted through the resealable member 126 and the resilient base 112 inorder to draw gas from the sealed vial as the liquid medicament isdeposited within the chamber of the vial. Once the medicament has beendeposited within the chamber of the vial, the needles 140 and 142 arewithdrawn from the cap 110, and as described further below, a heat orother energy source is applied to the portions of the resealable member126 punctured by the needles 140 and 142 to, in turn, seal the puncturedareas and hermetically seal the medicament within the vial.

In FIGS. 4 through 8 another resealable cap embodying the presentinvention is indicated generally by the reference numeral 210. Theresealable cap or stopper 210 is essentially the same as the cap 110described above, and therefore like reference numerals preceded by thenumeral “2” instead of the numeral “1” are used to indicate likeelements. As shown best in FIGS. 4 and 6, the base 212 of the capdefines on the interior side of its upper peripheral wall 217 an annulargroove 230. As shown best in FIGS. 4 and 7, the resealable member 226defines on the peripheral surface of its base 232 an annular raisedportion or protuberance 224 dimensioned to be frictionally receivedwithin the corresponding annular groove 230 of the base 212 to therebysecure the resealable member to the base. As shown in FIG. 6, the base212 further defines on the exterior side of its lower peripheral wall215 a plurality of raised annular portions or protuberances 244 axiallyspaced relative to each other for frictionally engaging the interiorwall of the vial 214 to thereby secure the cap within the vial andfacilitate maintaining a hermetic seal between the cap and vial. Asshown best in FIGS. 7 and 8, the resealable member 226 defines on itstop surface an annular raised portion or protuberance 246 defining acircular surface portion 248 therein for receiving a filling needle orlike instrument, as described further below. As shown in FIG. 5, thelocking or crimping ring 234 defines a central aperture 250 in its upperside for receiving therethrough the annular raised portion 246 of theresealable member 226.

Preferably, the resealable cap 210 and vial 214 are assembled and thelocking ring 234 is crimped in place as described above and shown inFIG. 4 prior to introducing any medicament or other fluid into the vial.Then, one or more of the empty cap/vial assemblies of the presentinvention may be enclosed, sterilized, and transported in accordancewith the teachings of the present inventor's commonly owned U.S. Pat.No. 5,186,772, entitled “Method Of Transferring Articles, TransferPocket And Enclosure”, and/or U.S. patent application Ser. No.10/421,249, entitled “Transfer Port and Method For Transferring SterileItems”, filed Sep. 10, 2002, each of which is hereby expresslyincorporated by reference as part of the present disclosure. The emptycap/vial assemblies are placed in an internal bag or “pocket” which isclosed and, if desired, provided with a sterilization indicator. Then,the internal pocket is placed within a transfer pocket including asealing frame defining an annular groove on a peripheral surfacethereof. The transfer pocket is stretched over the surface of the frameand closed by an elastic band overlying the transfer pocket and receivedwithin the peripheral groove. The transfer pocket likewise may includetherein a sterilization indicator. Preferably, the assembled transferand internal pockets are sealed within an “external” pocket and theassembled pockets are subject to sterilization, such as by exposure togamma radiation, to sterilize the pockets and the empty cap/vialassemblies within the pockets. The transfer pockets can then be used tostore and/or transport the sterilized assemblies to a filling systemwithout contaminating the sterilized assemblies.

As further described in the above-mentioned patent and patentapplication, the filling system is located within a sterile enclosure,and the empty vials are introduced into the enclosure by removing anddiscarding the external pocket, and connecting the sealing frame of thetransfer pocket to a window or transfer port of the enclosure. Asfurther disclosed in the above-mentioned patent and patent application,an adhesive material is preferably superimposed on the sealing frame forsecuring the transfer pocket to the transfer port of the filling systemenclosure. Prior to releasing the cap/vial assemblies into the fillingsystem enclosure, the sterilization indicators are preferably checked inorder to ensure that the sterile condition of the vial/cap assemblieswere maintained throughout storage and transfer. As described in theabove-mentioned patent and patent application, the portion of thetransfer pocket overlying the frame is then cut away and simultaneouslysterilized along the trimmed surfaces to destroy any microorganisms orgerms thereon, and to allow the internal pocket to be received throughthe transfer port and into the enclosure.

Once received within the enclosure, the internal pocket is opened andthe empty cap/vial assemblies are removed and loaded into a fillingmachine located within the sterile enclosure. Once loaded into thefilling machine, the resealable member 226 of each empty cap/vialassembly may be sterilized again in order to further ensure that nocontaminates enter the vial during the filling process. In accordancewith some embodiments of the present invention, the resealable members226 are sterilized at this stage by either direct heat cauterization orlaser or other radiation cauterization.

As shown in FIGS. 9A through 9C, an apparatus for cauterizing theresealable caps by application of heat thereto is indicated generally bythe reference numeral 252. The apparatus 252 comprises a housing 254mounted over a vial support 256. The vial support 256 may be adapted tohold a single vial, or preferably, is adapted hold a plurality of vials.The embodiment of the support adapted to hold a plurality of vialsdefines a channel 258 for receiving therein the vials, and a pair ofopposing shoulders 260 formed at the upper edge of the channel forsupporting thereon the flange 220 of the vial. If desired, a vibratorydrive (not shown) may be drivingly connected to the support 256 tovibrate the support and, in turn, move the vials through the channel ata predetermined rate. However, as may be recognized by those skilled inthe pertinent art based on the teachings herein, any of numerousdifferent drive systems that are currently, or later become known, maybe equally employed to move the vials through the filling machine.

The housing 254 defines a peripheral sealing surface 262 formed on thefree end of the housing for sealingly engaging the upper flange surface236 of each locking member 234. As shown best in FIG. 9B, the peripheralsealing surface surrounds the aperture 250 formed through the lockingmember and exposing the penetrable region 248 of the resealable member226 of the cap. Preferably, the peripheral sealing surface 262 forms asubstantially fluid-tight seal between the housing and the cap. Aheating surface 264 projects outwardly from the free end of a centralsupport 266 of the housing for contacting the penetrable surface 248 ofthe resealable member and cauterizing the surface. An annular conduit268 extends about the periphery of the heating surface 264 and iscoupled in fluid communication to a vacuum source 270 for drawing airthrough the conduit and away from the cauterized surface 248, asindicated by the arrows in the Figures. The housing 254 is drivinglyconnected to a drive source 272 for moving the housing and thus theheating surface 264 into and out of engagement with the exposedpenetrable surface portion 248 for cauterizing the surface, as indicatedby the arrows in the Figures. As may be recognized by those skilled inthe pertinent art based on the teachings herein, the drive source 272may take the form of any of numerous different types of drive sourcesthat are currently, or later become known, for performing the functionof the drive source as described herein, such as a pneumatic drive, or asolenoid-actuated or other type of electric drive. Similarly, theheating surface 264 may take any of numerous different shapes andconfigurations, and may be heated in any of numerous different ways thatare currently or later become known, such as by an electric resistanceheater (or “hot wire”). Preferably, however, the heating surface 264defines a surface shape and contour corresponding to the desired shapeand contour of the penetrable surface region 248 of the cap.

In the operation of the apparatus 252, and as shown typically in FIG.9A, each vial is first introduced into the cauterizing station with thepenetrable surface region 248 of the resealable member 226 aligned withthe heating surface 264. Then, the drive source 272 is actuated to drivethe housing 254 downwardly until the peripheral sealing surfaces 262sealingly engage the upper flange surface 236 of the respective lockingmember 234, and the heating surface 264 simultaneously engages theexposed penetrable surface portion 248 of the resealable member 226. Theheated surface 264 is maintained at a predetermined temperature, and isheld in contact with the exposed surface portion 248 for a predeterminedtime period, sufficient to cauterize the exposed surface portion. Oneadvantage of the construction of the resealable member 226 as shown inFIGS. 7 and 8, is that the cauterization process deforms the annularprotuberance 246 into a contour conforming to that of the heatedsurface, thus allowing an operator (or optical or other automaticsensing system) to visually determine whether each cap has been properlycauterized prior to filling. As shown in FIG. 9C, after cauterizing theexposed surface, the drive source 272 is actuated to drive the housing254 upwardly and out of engagement with the cap, another vial is movedunder the housing, and the process is repeated until all desired vialsare cauterized. As described further below, upon exiting the cauterizingstation of FIGS. 9A through 9C, the vials are preferably then moved intoa filling station to promptly fill the sterilized vials. Thecauterization and filling stations are preferably mounted within asterile enclosure with a laminar gas flow through the enclosure tofacilitate maintaining the sterile conditions, such as described in U.S.Pat. No. 5,641,004 to Daniel Py, issued Jun. 24, 1997, which is herebyexpressly incorporated by reference as part of the present disclosure,or described in connection with the embodiments below.

In one embodiment of the present invention, the temperature of theheating surface is within the range of approximately 250° C. to 300° C.,and the cycle times (i.e., the time period during which the heatingsurface is maintained in contact with the exposed surface 248 of theresealable member) are within the range of approximately 1.0 to 3.0seconds. The present inventor has determined that these temperatures andcycle times may achieve at least approximately a 6 log reduction inbio-burden testing to thereby effectively sterilize the surface.

In FIG. 10, an alternative apparatus for cauterizing the resealable capsis indicated generally by the reference numeral 274. The apparatus 274differs from the apparatus 252 of FIGS. 9A through 9C in that thethermal energy required for sterilizing the filling area of theresealable member is supplied by a laser (referred to herein as “lasercauterization”). The laser cauterization apparatus 274 comprises a laseror other suitable radiation source 276 optically coupled to a scanningmirror 278 mounted over the vial/cap assembly. Although not shown inFIG. 10, the vials are preferably mounted within the same type ofsupport as shown in FIGS. 9A through 9C in order to allow the resealablecaps to be rapidly cauterized in succession prior to filling each vialwith medicament, as described further below.

In one embodiment of the present invention, the laser 276 is acommercially available CO₂ or YAG laser. The CO₂ laser operates at awavelength of approximately 10.6 μm. At this wavelength, absorption ofthe laser energy is governed by the electrical conductivity of thematerial. Therefore, an insulating material, such as the elastomericmaterial of the resealable member 226, absorbs and converts most of theincident energy into thermal energy to cauterize the receiving surface248. The YAG laser operates at wavelength of approximately 1.06 μm. Atthis frequency, absorption is governed by the lattice atoms. Thus, aclear or transparent polymer with little ionization would be permeableto the laser beam. Accordingly, when employing a YAG laser, it isdesirable to add a colorant to the elastomeric material of theresealable member in a manner known to those of ordinary skill in thepertinent art in order to enhance its absorption of the laser energy. Asignificant advantage of the YAG laser is that the superficial layer ofthe penetrable region of the resealable member, and any germs, bacteriaor other contaminants thereon, are transformed into plasma to rapidlyand thoroughly sterilize the effected surface. If necessary, aUV-filtration coating may be applied to the surfaces of the enclosurefor the apparatus of the invention to prevent the operators fromreceiving any unnecessary UV exposure.

The present inventor has demonstrated that beam energies in the range ofapproximately 15 to 30 W are sufficient to effectively cauterize thesurface 248 of the elastomeric resealable member. In addition,bio-burden testing has demonstrated that laser energies of approximately20 W or greater may achieve about a 6.0 log reduction. At theseenergies, the apparatus of the present invention may effectivelysterilize the surface 248 within a cycle time of approximately 0.5seconds. Accordingly, a significant advantage of the laser cauterizationapparatus and method of the present invention is that they may involvesignificantly shorter cycle times than various direct heat methods. Yetanother advantage of the laser cauterization of the present invention,is that it involves both a non-contact method and apparatus, andtherefore there is no need to be concerned with the cleaning of acontact head or like heating surface.

Turning to FIG. 11, after direct heat or laser cauterization of theresealable member 226 of each vial, the vial is moved within the support256 (such as by vibratory drive) into a filling station 280. The fillingstation 280 includes a needle or like injection member 282 reciprocallymounted over the support 256, as indicated by the arrows in FIG. 11, andaxially aligned with the penetrable region 248 of the resealable member226 of each vial/cap assembly passing therethrough. A drive source 284is drivingly connected to the needle 280 for reciprocally driving theneedle 282 into and out of engagement with each cap 210. A medicament orother formulation reservoir 286 is coupled in fluid communication withthe needle 282 for introducing a predetermined medicament or otherformulation through the needle and into the vial. In one embodiment ofthe present invention, the needle 282 defines a plurality of fluidconduits therein, including a first fluid conduit 288 for injecting thepredetermined medicament or other formulation into the vial, asindicated by the arrow in FIG. 11, and a second fluid conduit 290coupled in fluid communication with a vacuum source 292 for withdrawingair or other gases from the interior cavity 216 of the vial prior toand/or during the filling of the cavity with the medicament or otherformulation. In the illustrated embodiment of the present invention, theneedle 282 is a “double lumen” needle, defining a central fluid conduit288 for injecting the predetermined medicament or other formulation intothe vial, and an outer annular fluid conduit 290 for drawing thedisplaced air or other gases out of the interior cavity of the vial.

As shown in FIGS. 12A through 12D, after filling the vial with themedicament or other formulation and withdrawing the needle 282 from thecap 210, the penetrated region of the cap defines a needle hole 294along the path of the withdrawn needle (FIG. 12B). Upon withdrawing theneedle, the vulcanized rubber and/or thermoplastic material of the capis sufficiently resilient to close upon itself in the penetrated regionand thereby maintain the vial in a sealed condition. However, asdescribed above, vapors, gases and/or liquid may be allowed over time topass through the needle hole, and therefore each vial/cap assembly ispassed through a sealing station, as shown typically in FIG. 12C, toheat seal the resealable portion 226 of the cap promptly afterwithdrawing the needle therefrom. As shown typically in FIG. 12C, aheated member or surface 264 is reciprocally mounted over, and axiallyaligned with the penetrable region 248 of the vial/cap assembly receivedwithin the filling station. A drive source 272 is drivingly connected tothe heated member 264 to reciprocally drive the heated member into andout of engagement with the resealable member of each cap. As showntypically in FIG. 12C, the heated member 264 is maintained at asufficient temperature, and maintained in engagement with the penetratedregion of the resealable member 226 to fuse the elastomeric material andhermetically seal the needle hole 294. As a result, and as showntypically in FIG. 12D, the needle hole is eliminated from the exteriorregion of the resealable member to thereby maintain a hermetic sealbetween the cap and vial.

As may be recognized by those skilled in the pertinent art based on theteachings herein, the drive source and heating member/surface of FIGS.12A through 12D may take the form of any of numerous different drivesources and heating members as described above. As indicated typicallyin FIG. 12C, however, the heating member 264 may define a smaller widththan the heating member/surface described above for cauterizing thepenetrable region of the cap prior to filling. In addition, thetemperature of the heating member 264 for sealing may be higher thanthat of the heating member described above in order to rapidly melt andseal the penetrated region. One advantage of the resealable cap of thepresent invention, is that the base thermally insulates the heatedregion from the medicament in the vial to thereby maintain themedicament in the vial within an appropriate temperature rangethroughout the cauterization and heat sealing processes and therebyavoid any thermal damage to the medicament.

Alternatively, and as shown in FIGS. 13A through 13C, the laser source276 and scanning mirror 278 may be employed to heat seal the penetratedregion 294/248 of the resealable member. Accordingly, the same type oflaser source 276 and scanning mirror 278 as described above may beemployed in the heat sealing station to perform this function, oralternatively, and as described further below, a different type of lasersystem may be employed. In one embodiment of the present invention, aCO₂ laser of approximately 50 W is employed to seal a regionapproximately 0.10 inch in diameter in the resealable cap.

FIG. 14 shows a vial assembly according to another embodiment of thepresent invention. The vial assembly is designated generally byreference numeral 1000, with resealable cap assembly 1010. Vial assembly1000 has a cylindrical body defining a chamber 1016 for storing apredetermined medicament, a snap-on base 1013, and a neck 1014. The cap1010 comprises a cap or stopper member 1012, a cap or locking ring ormember 1050 and a snap-off, tamper-proof cover 1040. The stopper member1012 of the cap defines a peripheral flange 1018 which is adapted andconfigured for engagement with the neck 1014 of the storage vial.Stopper member 1012 provides a first primary seal for containing thepredetermined medicament within the interior chamber of vial body. Ascan be seen, the neck 1014 of the vial defines a pointed annularprotuberance 1017 that projects axially into the overlying stoppermaterial to thereby further effectuate a hermetic seal between thestopper and vial.

Cap or locking member 1050 has an outer peripheral flange 1052 thatdefines a shoulder 1054 on an inner surface thereof. Shoulder 1054 isadapted and configured for interlocking engagement with lower surface1020 of neck 1014. Cap 1050 is made from a relatively flexible,non-metallic material, such as plastic. Cap or locking member 1050defines a central aperture that allows stopper member 1012 to beaccessed therethrough by a needle or like device. Cover 1040 isconfigured to overlie the central aperture of locking member 1050 andengage with locking member 1050, thereby protecting the exposed stoppermaterial. In the embodiment shown herein, cover 1040 is engaged withlocking member 1050 by means of a press-fit. Cover 1040 further defineson its underside a pointed annular protuberance 1057 that is pressedinto engagement with the adjacent stopper material to thereby effectuatea hermetic seal between the cover 1040 and stopper 1012. Preferably,cover 1040 cannot be removed from the vial without breaking the cover,thus providing a further tamper-resistant feature. Alternatively, thetamper resistant feature can be created by using ultrasonic welding,adhesion, or any other connection technique to engage cover 1040 withlocking member 1050 so that once removed, cover 1040 can not bere-engaged with locking member 1050.

FIG. 15 shows another embodiment of a vial assembly indicated generallyby the reference numeral 1100. The vial 1100 is similar in many respectsto the vial described above with reference to FIG. 14, and thereforelike reference numerals preceded by the numeral “11” instead of numeral“10” are used to indicate like elements. The primary difference of thevial 1100 in comparison to the vials described above is that the lockingmember 1110 is welded, such as by ultrasonic welding, to the neck 1114of the vial body. In addition, the flip-top or cover 1140 is tackwelded, such as by ultrasonic welding, to the locking member 1150. Thestopper 1112 defines an annular flange 1118, the neck 1114 of the vialbody defines a pointed annular protuberance 1117 that projects into oneside of the stopper flange 1118, and the locking member 1150 definesanother annular protuberance 1119 that projects into the opposite sideof the stopper flange 1118. Thus, the annular protuberances 1117 and1119 define continuous, annular sealing surfaces that facilitate ineffectuating a gas-tight or hermetic seal between the stopper and vialbody. The neck 1114 defines on its axial face a pointed annularprotuberance 1121 that is received within a corresponding annular recess1123 defined in the underside of the locking member 1150. The annularprotuberance 1121 is fused to the locking member 1150 within the annularrecess 1123 by ultrasonic welding, for example, to thereby fixedlysecure the locking member to the vial body. In addition, the annularweld preferably defines a hermetic or gas-tight seal between the lockingmember and vial body to further effectuate a gas-tight or hermetic sealbetween the interior of the vial and the ambient atmosphere.

The locking member 1150 further defines on its distal end a plurality ofdiscrete radially-extending protuberances 1166 received withincorresponding recesses 1168 formed within the underside of the lockingmember 1140. The protuberances 1166 are fused to the cover 1140 withinthe recesses 1168 by, for example, ultrasonic welding, to thereby definea plurality of frangible connections between the cover 1140 and lockingmember 1150. Alternatively, protuberances 1166′ may be formed at thebase of the flange 1142 of the cover and may be fused withincorresponding recesses 1168′ formed within the annular recess 1170 ofthe locking member. The base of the vial body may define a pointedannular protuberance 1115 that is received within a correspondingannular recess formed in the base 1113 for fixedly securing the base tothe body, such as, for example, by ultrasonic welding.

Vial assemblies of the type illustrated in FIGS. 14 and 15 are disclosedin further detail in U.S. patent application Ser. No. 10/655,455,entitled: “Sealed Containers and Methods of Making and Filling Same”,filed Sep. 3, 2003, which is hereby expressly incorporated by referencein its entirety as part of the present disclosure.

One advantage of the resealable stopper and vial assemblies of FIGS. 14and 15 is that the covers 1040, 1140 may be hermetically sealed to theunderlying locking members 1050, 1150 to thereby seal the stoppers 1012,1112 within the locking members 1050, 1150 and covers 1040, 1140 andwith respect to the ambient atmosphere. In accordance with one aspect ofa preferred embodiment of the present invention, the overlying lockingmembers and covers can be formed of relatively rigid materials and/or ofmaterials having relatively high resistances to moisture and vaportransmission in comparison to the material of the resealable stopperitself, in order to facilitate preventing the loss of any medicament orother substance contained within the vial or other containertherethrough, or the ingress of moisture or vapor into the vial or othercontainer, during, for example, storage, transportation and/or productshelf life.

Thus, in the currently-preferred embodiments of the present invention,each sealable cap or stopper 110, 210, 1012, 1112 is formed of athermoplastic material defining a needle penetration region that ispierceable with a needle to form a needle aperture therethrough, and isheat resealable to hermetically seal the needle aperture by applyinglaser radiation at a predetermined wavelength and power thereto. Eachcap or stopper 110, 210, 1012, 1112 includes a thermoplastic body 126,226, 1012, 1112 defining (i) a predetermined wall thickness in an axialdirection thereof, (ii) a predetermined color and opacity thatsubstantially absorbs the laser radiation at the predeterminedwavelength and substantially prevents the passage of the radiationthrough the predetermined wall thickness thereof, and (iii) apredetermined color and opacity that causes the laser radiation at thepredetermined wavelength and power to hermetically seal the needleaperture formed in the needle penetration region thereof in apredetermined time period and substantially without burning the needlepenetration region and/or the cover portion of the cap (i.e., withoutcreating an irreversible change in molecular structure or chemicalproperties of the material). In some embodiments, the predetermined timeperiod is approximately 2 seconds, is preferably less than or equal toabout 1.5 seconds, and most preferably is less than or equal to about 1second. In some of these embodiments, the predetermined wavelength ofthe laser radiation is about 980 nm, and the predetermined power of eachlaser is preferably less than about 30 Watts, and preferably less thanor equal to about 10 Watts, or within the range of about 8 to about 10Watts. Also in some of these embodiments, the predetermined color of thematerial is gray, and the predetermined opacity is defined by a darkgray colorant (or pigment) added to the stopper material in an amountwithin the range of about 0.3% to about 0.6% by weight.

In addition to the thermoplastic materials described above, thethermoplastic material may be a blend of a first material that ispreferably a styrene block copolymer, such as the materials sold undereither the trademarks KRATON or DYNAFLEX, such as DYNAFLEXG2706-10000-00, or GLS 230-174 (Shore A=30), and a second material thatis preferably an olefin, such as the materials sold under either thetrademarks ENGAGE or EXACT, such as EXACT 8203, or GLS 230-176 (ShoreA=42). In some embodiments of the invention, the first and secondmaterials are blended within the range of about 50:50 by weight topreferably about 90:10 by weight, and most preferably about 90:5 byweight (i.e., first material:second material). The benefits of thepreferred blend over the first material by itself are improved water orvapor barrier properties, and thus improved product shelf life; improvedheat sealability; a reduced coefficient of friction; improvedmoldability or mold flow rates; and a reduction in hystereses losses.

Alternatively, the thermoplastic material of the resealable stoppers ofthe invention may take the form of a styrene block copolymer sold by GLSCorporation of McHenry, Illinois under the designation LC 254-071. Thistype of styrene block copolymer compound exhibits approximately thefollowing physical properties: (i) Shore A Hardness: about 28-29; (ii)Specific Gravity: about 0.89 g/cm³; (iii) Color: approximately grey todark grey; (iv) 300% Modulus, flow direction: about 181-211 psi; (v)Tensile Strength at Break, flow direction: about 429-498 psi; (vi)Elongation at Break, flow direction: about 675%-708%; and (vii) TearStrength, flow direction: about 78-81 lbf/in.

In each of these embodiments of the present invention, the predeterminedcolor and opacity of the thermoplastic is defined by a grey colorantthat is provided in an approximately 3% color concentrate (i.e., thereis an approximately 33:1 ratio of the concentrate to the natural resinor TPE). The color concentrate contains about 88.83% carrier or baseresin, the remainder is pigment, and the pigment is grey carbon black.Thus, the pigment is about 0.34% by weight of the resultingthermoplastic.

In addition, if desired, a lubricant of a type known to those ofordinary skill in the pertinent art may be added to or included withineach of the above-mentioned thermoplastic compounds, in order to preventor otherwise reduce the formation of particles upon penetrating theneedle penetration region of the thermoplastic portion with a needle orother filling member. In one embodiment of the present invention, thelubricant is a mineral oil that is added to the styrene block copolymeror other thermoplastic compound in an amount sufficient to prevent, orsubstantially prevent, the formation of particles upon penetrating samewith the needle or other filling member. In another embodiment of thepresent invention, the lubricant is a silicone, such as the liquidsilicone sold by Dow Corning Corporation under the designation “360Medical Fluid, 350 CST”, or a silicone oil, that is added to the styreneblock copolymer or other thermoplastic compound in an amount sufficientto prevent, or substantially prevent, the formation of particles uponpenetrating same with the needle or other filling member. In one suchembodiment, the silicone oil is included in an amount within the rangeof about 0.4% to about 1% by weight, and preferably within the range ofabout 0.4 to about 0.6% by weight, and most preferably within the rangeof about 0.51 or about 0.5% by weight.

As described further below, the configuration of the needle that ispenetrating the stopper, the friction forces created at theneedle/stopper interface, and/or the needle stroke through the stopperalso can be controlled to further reduce or substantially prevent theformation of particles upon penetrating the stoppers with the needles.

In accordance with a further aspect of the present invention, the needlepenetrable and laser resealable stopper comprises: (i) a styrene blockcopolymer, such as any such styrene block copolymers described above,within the range of about 80% to about 97% by weight (e.g., 95% byweight as described above); (ii) an olefin, such as any of the ethylenealpha-olefins, polyolefins or olefins described above, within the rangeof about 3% to about 20% by weight (e.g., about 5% as described above);(iii) a pigment or colorant added in an amount sufficient to absorb thelaser energy, convert the radiation to heat, and melt the stoppermaterial, preferably to a depth equal to at least about ⅓ to about ½ ofthe depth of the needle hole, within a time period of less than about 2seconds, more preferably less than about 1.5 seconds, and mostpreferably less than about 1 second; and (iv) a lubricant, such as amineral oil, liquid silicone, or silicone oil as described above, addedin an amount sufficient to substantially reduce friction forces at theneedle/stopper interface during needle penetration of the stopper to, inturn, substantially prevent particle formation.

In accordance with a further aspect of the present invention, inaddition controlling one or more of the above-mentioned parameters toreduce and/or eliminate the formation of particles (i.e., including thesilicone oil or other lubricant in the thermoplastic compound, andcontrolling the configuration of the needle, the degree of friction atthe needle/stopper interface, and/or the needle stroke through thestopper), the differential elongation of the thermoplastic components ofthe resealable stopper is selected to reduce and/or eliminate theformation of particles.

Thus, in accordance with a further aspect of the present invention, theneedle penetrable and laser resealable stopper comprises: (i) a firstthermoplastic material within the range of about 80% to about 97% beweight and defining a first elongation; (ii) a second thermoplasticmaterial within the range of about 3% to about 20% by weight anddefining a second elongation less than the elongation of the firstmaterial; (iii) a pigment or colorant added in an amount sufficient toabsorb the laser energy, convert the radiation to heat, and melt thestopper material, preferably to a depth equal to at least about ⅓ toabout ½ of the depth of the needle hole, within a time period of lessthan about 2 seconds, more preferably less than about 1.5 seconds, andmost preferably less than about 1 second; and (iv) a lubricant, such asa mineral oil, liquid silicone, or silicone oil as described above,added in an amount sufficient to substantially reduce friction forces atthe needle/stopper interface during needle penetration of the stopperto, in turn, substantially prevent particle formation.

In accordance with a further aspect of the present invention, the firstmaterial defines a lower melting point (or Vicat softening temperature)than does the second material. In some of the embodiments of theinvention described herein, the first material is a styrene blockcopolymer, such as any of the styrene block copolymers described above,and the second material is an olefin, such as any of the ethylenealpha-olefins, polyolefins or olefins described above. Also inaccordance with the currently preferred embodiments of the presentinvention, the first material defines an elongation of at least about75% at 10 lbs force (i.e., the length increases by 70% when subjected toa 10 lb force), preferably at least about 85%, and most preferably atleast about 90%; and the second material defines an elongation of atleast about 5% at 10 lbs force, preferably at least about 10%, and mostpreferably at least about 15%, or within the range of about 15% andabout 25%. With respect to the above-mentioned materials, the elongationof each at 10 lbs force is approximately as follows: (1) GLS 230-176(Shore A-42)—14.35% to 16.42%; (2) Exact 8203 (Shore A=40)—17.87 to19.43%; (3) GLS 230-174 (Shore A=30)—81.67% to 83% (about 9 to 9.5 lbsforce); and (4) Dynaflex G2706 (Shore A=30)—76.85 to 104.95%. Inaddition, the Vicat softening point or temperature for Engage 8400 isabout 41° C., and for Exact 8203 is about 51° C.

As described further below, the currently preferred embodiment of theneedle employed to penetrate the stoppers in accordance with the presentinvention preferably defines a conically-pointed, non-coring tip (i.e.,a “pencil point” tip), wherein the included angle of the tip incross-section is within the range of about 15° to about 25°, preferablyabout 18° to about 22°, and most preferably about 20°. The smooth,sharply-pointed, gradually increasing angle of the needle tip allows fora relative smooth, and gradual expansion of the needle hole uponpenetrating the stopper. Further, the memory of the preferredthermoplastic blends cause the needle hole to substantially close onitself upon withdrawing the needle therefrom, thus reducing therequisite area of impingement by the laser beam for resealing, andreducing cycle time. In addition, this further reduces the possibilityof contaminating the interior of the vial between needle filling andlaser resealing. If desired, the stopper surface may be Teflon coated orotherwise coated with a low-friction material to further reducefriction, and thus the formation of particles, at the needle/stopperinterface. The needle tip further defines axially oblong flow apertureson opposite sides of the needle relative to each other. In the currentlypreferred embodiment, the needle is about 15 gage (i.e., 0.072 inchdiameter).

Preferably the needle/stopper interface is treated to reduce the degreeof friction therebetween to further reduce the formation of particlesduring the needle stroke. In one embodiment of the present invention,the needle is tungsten carbide carbon coated. In another embodiment, theneedle is electro-polished stainless steel. In another embodiment, theneedle is Teflon coated (although this embodiment gave rise to greaterfriction forces at the needle/stopper interface than did the tungstencarbide carbon coated embodiment). In yet another embodiment, the needleis titanium coated to reduce friction at the needle/stopper interface.Further, in some embodiments of the present invention, the depth ofstroke of the needle is set to further reduce the formation ofparticles. In one such embodiment, at the bottom of the needle stroke,the needle flow apertures are spaced below the bottom wall of thestopper and adjacent or contiguous thereto (i.e., the upstream end ofeach hole is adjacent to the inside surface of the bottom wall of thestopper). In one such embodiment, the needle tip penetrates beyond theinside surface of the bottom wall of the stopper to a depth within therange of about 1 to about 5 cm, preferably within the range of about 1to about 3 cm, and most preferably about 1.5 centimeters.

Each of the vials of the present invention may be made of any ofnumerous different materials that are currently, or later become knownfor making vials or other dispensers employing the resealable stoppersof the present invention. For example, in some embodiments of thepresent invention, the vials are made of glass. In othercurrently-preferred embodiments of the present invention, the vials aremade of a thermoplastic material, such as the thermoplastic materialsold under the trademark TOPAS by Ticona Corp. of Summit, N.J. In someembodiments of the present invention, the TOPAS material is sold underany of the following product codes: 5013, 5513, 6013, 6015, and 8007,and is a cyclic olefin copolymer and/or cyclic polyolefin.

As may be recognized by those skilled in the pertinent art based on theteachings herein, the specific formulations of the polymeric compoundsused to form the stoppers and the vials or other containers of thepresent invention can be changed as desired to achieve the desiredphysical characteristics, including sorption (both absorption andadsorption), and moisture-vapor transmission (“MVT”). For example, thewall thicknesses of the vials and/or stoppers can be increased orotherwise adjusted in order to provide an improved or otherwise adjustedMVT barrier. Alternatively, or in conjunction with such measures, theblend of components forming the thermoplastic compounds may be changedas desired to meet desired sorption levels with the particularproduct(s) to be contained within the vial, and/or to achieve desiredMVT characteristics. Still further, in those embodiments of theresealable stopper of the present invention employing multiple layers offusible and infusible materials, the relative thickness of the differentmaterials can be adjusted to, in turn, adjust the MVT characteristics ofthe stopper. As also may be recognized by those of ordinary skill in thepertinent art based on the teachings herein, the above-mentioned numbersand materials are only exemplary, and may be changed as desired orotherwise required in a particular system.

One advantage of the preferred embodiments of the present invention isthat the resealable portion 126, 226, 1012, 1112 of the cap or stoppermay be resealed following the deposit of medicament into the chamber,thereby rendering the end cap of the invention particularly suitable foruse with preservative-free medicaments, such as preservative-freevaccines. Accordingly, a further advantage of the preferred embodimentsof the present invention is that the medicament need not contain apreservative, and therefore the above-described drawbacks anddisadvantages of such preservatives can be avoided.

Another advantage of the preferred embodiments of the present inventionis that the medicament within the resealed chamber is not contaminatedor otherwise affected by impurities or other agents in the atmospherewhere the vial is stored or transported.

Another advantage of the present invention is that all components of thevial may be molded from thermoplastics or other plastic materials, thusfacilitating the manufacture of significantly safer, sterile, pyrogenfree vials in comparison to the prior art. For example, the stoppers andvials can be molded in machines located side-by-side (or otherwise inclose proximity to each other), wherein each molding machine is locatedunder a laminar flow hood (or both machines are located under the samelaminar flow hood), Then, the stoppers are assembled and sealed to therespective vials (or vice versa) promptly after molding (and while stillhot or at a bactericidal temperature) under the laminar flow hood by,for example, a suitable assembly fixture wherein a plurality of stoppersare brought into engagement with a plurality of vial bodies (or viceversa), or by a pick-and-place robot. As a result, the interiors of thesealed vials are sterile and pyrogen free promptly upon being moldedsubstantially without risk of contamination. The locking members alsocan be assembled to the vial bodies and stoppers at this time under thelaminar flow hood, or can be assembled at a later time, if desired.

FIG. 16 is representation of a conventional facility and method 1800 forsterile filling of medicaments intended for intravenous injection orother sterile substances. The conventional facility and method employs afirst area (e.g., a warehouse of class 100,000) for receiving medicamentand containers (e.g., vials and caps) to be filled. The facility andmethod further employs a series of progressively “cleaner” areas1802-1806, including an area 1806 (e.g., a class 1 area) where thecontainers are sterilized, filled, and sealed.

FIG. 17 is representation of a facility and method 1900 for sterilefilling of medicaments, in accordance with another aspect of the presentinvention. The facility and method 1900 includes a first area (e.g., awarehouse of class 100,000) for receiving medicament and bags 1907containing trays of sealed, sterile containers (e.g., vials and caps) tobe filled with medicament. Various tray-container arrangements are shownin FIGS. 29A-C. The facility and method further employs a series ofprogressively “cleaner” areas 1902-1904, including an area 1904 (e.g., aclass 100 area) where a filling machine 1910 for sterile filling (of thesterile sealed containers) is located, sometimes referred to hereinafteras a “sterile filling machine”. The bags 1907 containing the trays ofcontainers may arrive packed in boxes 1908 to help keep the sealed bags1907 clean and undamaged.

In some embodiments, each tray of containers arrives double or triplebagged rather than single bagged. The bagged trays of containers may,for example, be removed from the boxes in the area 1901. The baggedtrays of containers are thereafter transported through progressively“cleaner” areas 1902-1904 until reaching the sterile filling machine1910. If the trays of containers are double or triple bagged, one or twoof the bags may be removed prior to reaching the sterile filling machine1910. The tray of sealed sterile containers is thereafter transferredfrom the remaining bag to the sterile filling machine 1910 to be filledwith medicament and resealed.

In another embodiment, containers arrive prior to being sterilized andare thereafter sterilized, sealed, and bagged within the facility 1900and then transported to the sterile filling machine 1910 for filling andresealing. Either of the two above embodiments may employ one or more ofthe methods described above for transporting sealed sterile containers.In addition, the sterile filling machine may employ an e-beam, lasersterilization, and/or other type of pre-sterilization unit to sterilizeat least the penetrable surfaces of the resealable stoppers prior toneedle penetration, filling and laser resealing, as otherwise describedherein.

One advantage of the facility and method 1900 shown in FIG. 17 ascompared to the facility and method 1800 shown in FIG. 16 is that thefacility and method 1900 shown in FIG. 17 allow sterile filling withoutthe need for the class 10 area 1805 and the class 1 area 1806.

FIGS. 18-20 are perspective views of a sterile filling machine 2010 inaccordance with another aspect of the present invention. The fillingmachine 2010 may, for example, be used to introduce medicament though aresealable cap on a cap/vial assembly, and to thereafter reseal the cap.Other embodiments of the filling machine 2010 may be used to fill andseal other types of containers (including but not limited to other typesof vials or syringes), that may have resealable caps or stoppers thatare the same as or different than those described above, with medicamentor other substance(s) such as, for example, but not limited to,cosmetics or food products.

In this embodiment, the filling machine 2010 has an infeed unit 2012 anda fill unit 2014. As will be further described hereinafter, the infeedunit 2012 receives the containers (e.g., the vials, syringes or othercontainers) that are to be filled, and thereafter supplies thecontainers to the fill unit 2014, which in turn fills the containers. Anexample of a plurality of containers to be filled and sealed by thefilling machine 2010 are shown at 2015 (FIG. 20).

The infeed unit 2012 includes an infeed assembly 2016 and an infeedsupport structure 2018. Further details of the infeed assembly 2016 aredescribed hereinafter with respect to FIGS. 24, 25, 26A-26B, 27 and28A-28I. As shown in FIG. 20, the infeed support structure 2018 includesa frame 2020, two plates 2022, 2024 joined thereto, and side panels 2025connectable to the frame to enclose the interior thereof (FIGS. 18 and19). More particularly, as shown in FIG. 20, the upper plate 2022 isjoined to an upper portion of the frame 2020. The lower plate 2024 isjoined to a lower portion of the frame 2020. The upper plate 2022 has anoutwardly facing surface 2026 that supports the infeed assembly 2016.The lower plate 2024 has feet 2028 mounted thereto. The feet 2028 mayhave any form including but not limited to casters (as shown), wheels,or any combination thereof.

The fill unit 2014 includes a fill assembly 2030 and a fill supportstructure 2032. Further details of the fill assembly 2030 are describedhereinafter with respect to FIGS. 21-25, 26A-26B, 30A-30F, and 31A-31H.As with the support structure of the infeed unit, and as shown in FIG.20, the support structure of the fill assembly includes a frame 2034,two plates 2036, 2038, and side panels 2039 connected thereto (FIGS. 18and 19). As shown in FIG. 20, the upper plate 2036 is joined to an upperportion of the frame 2034. The lower plate 2038 is joined to a lowerportion of the frame 2034. The upper plate 2036 has an outwardly facingsurface 2040 that supports the fill assembly 2030. The lower plate 2038has feet 2042 mounted thereto. The feet 2042 may have any form includingbut not limited to casters (as shown), wheels, or any combinationthereof.

The filling machine 2010 further includes a barrier 2044 that restrictsmovement into and out of the filling machine. In this embodiment, thebarrier 2044 includes a frame 2046 and walls 2048 (or panels) supportedthereby. One or more of the walls 2048 may be transparent, or at leastsomewhat transparent, to provide visibility into the filling machine. Insuch instance, the transparent wall(s) may be adapted to limit thetransmissibility of particular wavelengths, so as to reduce thepossibility that emissions from any lasers within the filling machinecould accidentally cause harm to people in the vicinity of the fillingmachine. This may be carried out, for example, by tinting. As shown inFIGS. 18 and 28A, the infeed unit barrier 2048 may includes a pluralityof apertures 2049 spaced relative to each other throughout therespective panel of the barrier in order to allow the laterally orhorizontally directed laminar flow to exit the aseptic enclosure of theinfeed unit therethrough.

The barrier 2044 can be viewed as having a base portion 2049 and anupper portion 2051. The base 2049 is connected to the support structures2018, 2032 by way of support members (not shown). The upper portion 2051supports blower assemblies 2050, 2052. Each of these blower assemblies2050, 2052 includes a filter and a fan to produce a filtered airflowinto the filling machine. This filtered airflow causes the air pressurewithin the barrier 2044 to be somewhat greater than the air pressureoutside the barrier 2044. This pressure differential helps minimize thepossibility of airflow into the filling machine 2010, which in turnhelps prevent (or at least limit) the possibility that contaminants willget into the filling machine 2010. In some embodiments, the filter is ahigh efficiency filter such as, for example, a HEPA filter.

The base 2049 of the barrier 2044 and the support structures 2018, 2032are shaped and dimensioned so as to define clearances therebetween. Forexample, in the illustrated embodiment, the clearances are in the formof an approximately three inch gap between the periphery of the base andthe perimeter of the support structures 2018, 2032. These clearances, orvents, define a flow path through which the filtered airflow provided bythe blower assemblies 2050, 2052 exits the filling machine 2010. Thebarrier 2044, blower assemblies 2050, 2052, vents, and structureslocated within the barrier 2044 are preferably designed so as to helpensure that the filtered airflow has laminar flow characteristics, or atleast generally laminar flow characteristics (as opposed to turbulentflow characteristics), until exiting the filling machine 2010. Thelaminar flow characteristics help keep contaminants from entering thefilling machine through the vents and help clear out any dust orcontaminants that happen to get into the filling machine 2010, andthereby help maintain a “clean” environment within the filling machine2010.

The barrier 2044 is provided with one or more doors, e.g., door 2060,which can be opened to access the area within the barrier 2044. In thisembodiment, the door 2060 includes a lock and handle 2062 and is affixedto the frame of the barrier via hinges 2064. Notwithstanding, it shouldbe recognized that opening the door 2060 creates an opportunity forcontaminants to enter the filling machine 2010 from outside the barrier2044. Thus, it is generally undesirable to open the door 2060 after theinitial set up of the filling machine 2010. For this reason, the barrier2044 is provided with a transfer port 2066 and glove ports 2067-2069.The transfer port 2066 is of a type known to those of ordinary skill inthe pertinent art and allows materials to be introduced into the fillingstation without the need to open the door 2060 of the barrier 2044. Forexample, the transfer port can be used to remove old tubing and installfresh, sterile tubing between the pumps and needles between fillingoperations. Glove ports 2067-2069 allow an operator to performoperations within the filling machine 2010, without the need to open thedoor 2060. For example, the glove ports may be used to open and closethe interior door of the transfer port 2066, and to remove the oldtubing and install fresh tubing between the pumps and needles betweenfill operations. The glove ports 2067-2069 may be provided with sensorsthat produce a signal when an operator has his or her hands in the gloveports. Alternatively, a light or other radiation beam or curtain can beprovided between the glove ports and interior portions of the fillingmachine to sense movement of the gloves and produce a signal in responsethereto that can either warn the operator or terminate operation of themachine. In order to prevent injury to the operator, the signal may beused to initiate a shut down of the filling machine 2010 until thesensor determines that the operator's hands are removed from the gloveports 2067-2069. In some embodiments, the barrier 2044 includes a wall2071 (FIG. 28A) that limits airflow between the infeed unit 2012 and thefill unit 2014.

The filling machine 2010 further includes a plurality of pumps 2070,2072, 2074, 2076 (FIGS. 20 and 30F), a bank of laser sources 2080, 2082,2084, 2086 (FIG. 20), and a bank of IR sensor detector modules 2242,2244, 2246, 2248 (FIGS. 36 and 37A-37D), which are further discussedhereinafter. As shown in FIGS. 18 and 19, a cabinet 2097 is mounted onone side of the barrier 2044 and encloses the pump, laser sources andother electronic components or devices mounted therein.

In some embodiments, it may be desirable to provide means for foggingthe interior of the filling machine 2010 with a chemical to helpeliminate contaminants when the filling machine is initially set up, atsome selected points in time thereafter, and/or after some types ofevents that would require such fogging.

Referring to FIG. 24, the infeed unit 2012 includes a first portion 2100that resides outside of the barrier 2044 and a second portion 2102 thatresides inside the barrier 2044. Referring to FIGS. 27 and 28, the firstportion 2100 includes a shelf 2104, a clamp 2106, an infeed port 2108and handle 2110. The shelf 2104 is adapted to support a bagged tray ofcontainers prior to feeding the tray into the infeed unit. An example ofa tray of a containers 2105 is shown on the surface of the shelf 2104. Alid is shown on the tray of containers 2105; however, this is notrequired. Another embodiment of a tray arrangement that may be used toload vials or other containers into the infeed unit 2012 is shown inFIG. 29. As can be seen, the trays 2107 are stackable, and each trayincludes a base wall 2109 for supporting thereon the rows of vials, andvertically-extending end walls 2111 on opposite ends of the base wallrelative to each other. The end walls 2111 are hollow such that theupper ends of the end walls of one tray may be received within thehollow base of the end walls of another tray to stack the trays ofvials.

For clarity, the bag around the tray of containers is not shown in FIG.24. The clamp 2106 (FIGS. 27-28) is adapted to help transfer the tray ofcontainers 2105 from the first portion 2100 of the infeed unit to thesecond portion 2102 of the infeed unit without exposing the containersto unfiltered air from outside of the barrier. The infeed port 2108 maybe shaped and dimensioned to receive the tray of containers. The handle2110 is connected to a rod 2112, which is, in turn, connected to a firstsweeper arm 2114 provided on the second portion 2102 of the infeed unit.The handle can be moved in and out (as indicated by arrows 2116 in FIG.28) and can be turned (as indicated by arrows 2118 in FIG. 28). In someembodiments, the clamp 2106 opens by having one side of the secondportion 2122 rotate upwards, rather than sliding up and down.

As shown in FIG. 28, the clamp 2106 includes two clamp portions 2120,2122. Slidable connecting members 2124, 2126 connect the first portion2120 to the second portion 2122. Each portion 2120, 2122 has a clampingsurface 2128, 2130, respectively. Each clamping surface 2128, 2130defines one or more vacuum ports, e.g., vacuum port 2132. The vacuum ofthe ports are selectively connected to one or more vacuum source(s) (notshown).

As shown in FIG. 27, the second portion 2102 of the infeed unit 2012includes a first staging area 2136, a second staging area 2138, thefirst sweeper arm 2114 and a second sweeper arm 2115. As stated above,the first sweeper arm 2114 is connected to the rod 2112 which isconnected to the handle 2110. Thus, turning the handle 2110counter-clockwise causes the sweeper arm 2114 to rotate to a verticalposition. Turning the handle 2110 clockwise causes the sweeper arm 2114to rotate from the vertical position to the horizontal position. Movingthe handle 2110 in and out in the direction of the arrows 2116 (FIG. 28)causes the sweeper arm 2114 to move back and forth between the firststaging area 2136 and the second staging area 2138. More particularly,pushing the handle 2110 inward (toward the infeed unit 2012) causes thesweeper arm 2114 to move from the first staging area 2136 to the secondstaging area 2138. Pulling the handle 2110 outward (away from the infeedunit 2012) causes the sweeper arm 2114 to move from the second stagingarea 2138 to the first staging area 2136. In this embodiment, thecontainers are “diabolo” shaped vial/cap assemblies, as illustrated forexample in FIGS. 14 and 15. One advantage of this shape is that once thevial is upright, it is fairly stable and therefore tends to remain in anupright condition and not tip over.

The second portion 2012 of the infeed unit 2012 further includes ablower assembly 2139 (FIG. 22). The blower assembly 2139 provides afiltered airflow that exits through the infeed port 2108. The infeedunit 2102 is preferably designed so as to help ensure that the filteredairflow has laminar flow characteristics, or at least generally laminarflow characteristics (as opposed to turbulent flow characteristics),until exiting the infeed port 2108. As described above, and shown inFIG. 28A, the barrier panel 2048 on the inlet side of the infeed unitdefines a plurality of apertures 2049 spaced relative to each otherthroughout the respective panel to allow the laminar flow to exit theinfeed unit therethrough. The laminar flow characteristics help keepcontaminants from entering the filling machine through the infeed port2108 and help clear out any dust or contaminants that happen to get intothe filling machine 2010, and thereby help maintain a “clean”environment within the filling machine 2010.

In an alternative embodiment of the infeed unit 2012′ shown best inFIGS. 28A-28I, the upper portion 2030′ of the clamp 2106′ is pivotallymounted by a pair of hinges 2124′ to the frame 2046. Each clampingsurface 2128′, 2130′ includes a longitudinally extending vacuum slit2132′ (only one shown) that is coupled in fluid communication with avacuum source for releasably securing a respective wall of the traycontaining bag thereto. Thus, the second portion 2122′ of the clamp2106′ is pivotable toward and away from the first portion 2120′ to closeand open the clamp.

As shown in FIGS. 28B-28I, the infeed unit 2012′ includes a tray lifter2141′ that is mounted on pairs of opposing drive shafts 2143′ located onopposite sides of the first staging area 2136′ relative to each other.The drive shafts 2143′ are drivingly connected to a drive source (notshown), such as a servo-drive to move the lifter between raised andlowered positions. The lifter 2141′ includes a plurality of suction cups2145′ that are coupled in fluid communication to a vacuum source andface downwardly to releasably engage the cover of the tray locatedwithin the first staging area 2136′. As shown in FIGS. 28B and 28C, thetray lifter 2141′ is movable between a raised position (FIG. 28B) spacedabove the tray located within the first staging area 2136′ and a loweredposition (FIG. 28C) with the suction cups 2145′ engaging the uppersurface of the tray cover and releasably securing the tray coverthereto. As shown in FIG. 28D, the lifter 2141′ is driven upwardly tothe raised position to lift the tray cover away from the tray and vialsand thereby expose the vials for removal from the tray into the secondstaging area 2138′.

The first sweeper arm 2114′ is pivotally mounted and movable between adown position, as shown typically in FIG. 28B, and an up position, asshown typically in FIG. 28D. The first sweeper arm is driven by asuitable drive source (not shown), such as a servo-actuator, between thedown and up positions. Further, the first sweeper arm 2114′ is drivenhorizontally by a suitable drive source (not shown), such as aservo-drive, between a rearward position, shown typically in FIG. 28D,and a forward position (not shown) spaced adjacent to the infeed port2108 for sweeping the vials off of the tray and into the second stagingarea 2138′. As shown in FIG. 28D, after the lifter 2141′ lifts the traycover away from the vials, the first sweeper arm 2114′ is pivotedupwardly and driven from the rearward position (FIG. 28D), to theforward position adjacent to the infeed portion 2108. Then, in theforward position, the first sweeper arm 2114′ is pivoted into the downposition, and is then driven from the forward position to the rearwardposition to, in turn, sweep the vials off of the tray and into thesecond staging area, as shown in FIGS. 28E-28G. Then, when all of thevials are located in the second staging area, the second sweeper arm2115′ is driven laterally from a rearward position, as shown typicallyin FIG. 28G, to a forward position, as shown in FIG. 281, to move thevials from the second staging area, beneath the barrier 2017 extendingbetween the infeed unit and the filling unit, and onto the turntable2150 of the infeed unit.

Referring again to FIG. 24, the fill unit 2014 includes a transportsystem including a turntable 2150 and four star wheels 2152, 2154, 2156,and 2158. As will be further described below, the turntable 2150 isadapted to rotate in a counter-clockwise direction. The first and thirdstar wheels 2152, 2156 are adapted to rotate in the clockwise direction.The second and fourth star wheels 2154, 2158 are adapted to rotate inthe counter-clockwise direction. Examples of the containers filled bythis embodiment of the filling machine 2010 are indicated at 2015A,2015B, 2015C, 2015D, 2015E, and 2015F.

As shown in FIG. 30A, a first guide 2160 is provided at the periphery ofthe turntable 2150. This guide 2160 keeps the containers from fallingoff of the turntable 2150. A second guide 2162 is spaced apart from asection of the first guide to define a channel 2164 therebetween. Athird guide assembly (see FIG. 30A) includes a support member 2168 whichis disposed over the turntable 2150 and supports guides 2170, 2172 (seeFIG. 30A), which collectively steer the containers toward the channel2164 defined by the first and second guides 2160, 2162.

A fourth guide 2174 is provided at the periphery of the first star wheel2152. A fifth guide 2176 is provided at the periphery of the second starwheel 2154. A sixth guide 2178 is fed from (i.e., in communication with)the periphery of the third star wheel 2156 and transports containersthat have been successfully filled and sealed. A seventh guide 2180 isfed from the periphery of the fourth star wheel 2158 and transportscontainers that have not been successfully filled or not successfullysealed.

Each of the star wheels 2152, 2154, 2156, 2158 has a plurality ofrecesses along its peripheral surface that are adapted to receivecontainers. The first star wheel 2152 preferably has a saw-tooth likeperiphery 2190 that reduces the likelihood of jamming against containersas they are received from the channel 2164. FIG. 38 is an elevationalview of one embodiment of the first star wheel 2152. In such embodiment,the periphery of the first star wheel 2152 defines a plurality of teeth,e.g., 2191, 2192. Each tooth has a pointed end, e.g., 2193, 2194. Eachtwo successive teeth surround, on two opposite sides, a respective oneof the recesses adapted to receive a container. For example, in thisembodiment, teeth 2191, 2192 surround recess 2195. In this embodiment,the teeth and/or recesses are shaped and/or dimensioned such that theportion of the tooth that is substantially upstream and adjacent to thepoint defines a seat 2196 in which a respective container will rest. Inthis embodiment, the seat 2196 defines a surface that pushes against thecontainer. Other designs may of course also be employed.

Referring again to FIG. 26A, the recesses of the third and fourth starwheels 2156, 2158 are provided with vacuum ports which are selectivelyconnected to a vacuum source to thereby allow the third and fourth starwheels to carry containers as appropriate.

As shown best in FIGS. 30A and 31A-31H, a needle fill manifold 2200 isdisposed at a first position along the periphery of the second starwheel 2154. The needle fill manifold 2200 holds a plurality of needles,e.g., four needles 2202, 2204, 2206, 2208, which are used to delivermedicament into the containers. The needle manifold 2200 is drivinglymounted such that each needle is movable into and out of engagement withthe resealable stoppers to pierce the stoppers and fill the vials orother containers with a medicament or other substance to be containedtherein, and to then withdraw the needle upon filling the vial.Providing multiple needles makes it possible to fill multiple containersconcurrently. As shown in FIG. 31A-31H, each of the needles is in flowcommunication with a respective flexible tube 2212, 2214, 2216, 2218that connects the respective needle 2202, 2204, 2206, 2208 to arespective medicament source (not shown) through a respective one of thepumps 2070-2076 (FIG. 30F). Note that the medicament source may belocated inside the filling machine 2010 or outside of the fillingmachine. Note that bellows 2220 (FIG. 26A) may be provided on the shaftsthat drive the needles or needle manifold 2200 to seal the movable partsof the shafts. In some embodiments, the needle stroke length may beabout 1 inch.

A laser sealing and infrared (IR) sense manifold 2230 (see FIGS. 30A,36, 37A-37D) is disposed at a second position along the periphery of thesecond star wheel 2154, downstream of the needle fill manifold 2200. Thelaser sealing and IR sense manifold 2230 is not shown in certain otherfigures in order to preserve clarity. As shown typically in FIG. 36,this manifold 2230 holds a plurality of laser optics assemblies (e.g.,four laser optic assemblies 2232, 2234, 2236, 2238) along with aplurality of IR sensors (e.g., four IR sensors 2242, 2244, 2246, 2248).The laser optic assemblies are adapted to provide a laser beam to resealthe resealable caps or stoppers on the containers after needle filling.Each of the plurality of laser optic assemblies is mounted at arespective location near the periphery of the second star wheel 2154 fortransmitting a respective laser beam onto a respective resealablestopper to heat seal the needle aperture in the resealable stopper. Eachof the laser optic assemblies 2232, 2234, 2236, 2238 is connected to arespective fiber optic cable 2233 that connects the respective opticassembly 2232, 2234, 2236, 2238 to a respective laser source 2080, 2082,2084, 2086 (FIG. 20). Providing multiple fiber optic assemblies makes itpossible to reseal multiple containers concurrently.

In this embodiment, each of the plurality of IR sensor assemblies2242-2248 is mounted at a respective location near the periphery of thesecond star wheel 2154. As shown, the laser sources 2080-2086 aremounted outside of the enclosure 2044 to enable repair and/orreplacement of the laser sources without having to open the enclosureand/or otherwise risk contamination of the sterile enclosure. The IRsensors 2242-2248 detect the temperature of the needle penetrationregion of the resealable stopper achieved during laser resealing, andtherefore can be used to determine whether the stopper was sufficientlyreheated to achieve resealing. Each of the IR sensors 2242, 2244, 2246,2248 is connected to a respective IR sensor module 2090, 2092, 2094,2096 (FIG. 20). Providing multiple IR sensors enables the sterilefilling machine 2010 to sense the temperature of multiple containersconcurrently, for example, as they are being resealed. As describedabove, each laser source transmits a predetermined wavelength of laserradiation at about 980 nm, and the predetermined power of each laser ispreferably less than about 30 Watts, and preferably less than or equalto about 10 Watts, or within the range of about 8 to about 10 Watts. Inthe illustrated embodiment, each laser source is a semi-conductor diodelaser that outputs at about 15 Watts, and is fiber-optically coupledthrough a fiber-optic cable to respective collimating lens mounted overthe vials within the interior of the filling unit. One advantage ofmounting the laser sources outside of the enclosure is that they can beeasily repaired or replaced without having to access the interior of theenclosure.

Capacitor sensors (not shown) also may be provided along the peripheryof the second star wheel 2154, downstream of the needle fill manifold2200. Such sensor can be used to sense whether a container received anymedicament.

FIGS. 39A-39C show side elevational views of sequential steps employedin one embodiment to insert a tray of containers into the infeed unit2012. Referring now to FIGS. 39A-39C, in use, a bagged tray ofcontainers 2105 is placed on the shelf 2104. With the clamp 2106, 2106′open, one end of the bag 2107 is inserted through and beyond the openclamp thereby defining a portion 2109 that extends beyond and overhangsthe clamp. The end 2109 of the bag is then arranged so as to lay flat onthe surface 2128, 2128′ of the first clamp portion 2120, 2120′ and theclamp 2106, 2106′ is closed. With the clamp 2106, 2106′ closed, theoverhanging portion 2109 of the bag 2107 is cut off and discarded, andthe vacuum source is applied to the vacuum ports of the two clampportions 2120, 2122, 2120′, 2122′. The clamp 2106, 2106′ is then opened,and because of the vacuum applied to the vacuum ports, the cut end ofthe bag 2107 opens therewith. This is because the vacuum applied to thevacuum ports 2132, 2132′ causes the bottom side of the cut end of thebag to be releasably secured to the surface 2128, 2128′ of the firstclamp portion 2120, 2120′ and causes the top side of the cut end of thebag to be releasably secured to the surface 2130, 2130′ of the secondclamp portion 2122, 2122′.

After the clamp 2106, 2106′ and the cut end 2109 of the bag are open,force is applied to the tray 2105, through the other side of the bag, soas to push the tray through the open clamp, through the infeed port2108, and onto the first staging area 2136, 2136′. The blower 2139 (FIG.22) fills the open bag with sterile air and thus facilitates the openingof the bag and the release of the sterile trays and vials therefrom andinto the infeed unit. The vacuum is removed from the vacuum ports 2132,thereby releasing the bag 2107, which may then be discarded. As shown inFIG. 39C, the second portion 2122 of the clamp and the wall defining thetop of the infeed port 2108 hang low enough to block entry of theoverlying tray or lid that had been retaining the containers positionedon the tray. Alternatively, the overlying tray or lid is moved into theinfeed unit, and the lifter is actuated to lift the tray cover off thetray to expose the vials thereon.

After the tray 2105 is in the first staging area 2136, 2136′, and withreference to FIGS. 28B-28G, the first sweeper arm 2114, 2114′ isactuated so as to slide the containers off the tray and into the secondstaging area 2138, 2138′. The first sweeper arm 2114, 2114′ may beactuated manually, using the handle 2110, or automatically, as describedabove. With reference to FIGS. 28H and 281, the empty tray 2105 isthereafter removed from the infeed unit 2012, 2012′. After thecontainers are in the second staging area 2138, 2138′, the secondsweeper arm 2115, 2115′ is actuated so as to slide the containers intothe fill unit 2014, and onto the turntable 2150.

As stated above, in this embodiment, each container is a vial defining asubstantially “diabolo” shape formed by a base, a cap and a bodyextending between the base and cap, wherein the base and cap define adiameter or width that is greater than that of the body. The diaboloshape may facilitate securing and otherwise transporting the vialsthrough the filling machine 2010. Further, the “diabolo” shape of thevials facilitates transporting the vials or the star wheels or othertransporting mechanism without the need for a base surface to supportthe base of the vial. In addition, the diabolo shape facilitatessupporting the vial in the needle filling station and to hold the vialsin place when penetrated by the needles, as shown, for example, in FIG.31D.

After the containers are on the turntable 2150, they are guided by theguides 2170, 2172 (FIG. 30A) toward the turntable periphery and into asingle file relationship within the channel 2164. The recesses of thefirst star wheel 2152 receive containers from the channel 2164 andadvance the containers in a clockwise direction along the guide 2174,typically at predetermined rate.

The containers are transferred to the recesses of the second star wheel2154 as they reach the first or input end of the guide 2176. The secondstar wheel 2154 transports the containers along the guide 2176. Thesecond star wheel 2154 is indexed four positions and then paused for amomentary dwell. During the dwell, the needle manifold 2200 is drivendownward so as to drive the four needles 2202-2208 through theresealable stoppers on the four containers beneath the needle manifold2200. Medicament is thereafter delivered to the containers and themanifold is then driven up to thereby retract the four needles 2202-2208from the four stoppers. In one embodiment, the needles are initiallywithdrawn at a relatively slow speed to allow the vials to fill“bottom-up”; then, when the vials are filled, the needles are withdrawnat a relatively faster speed to quickly remove the needles and decreaseoverall cycle time. In another embodiment, the depth of stroke of theneedle is set to reduce or prevent the formation of particles. In onesuch embodiment, at the bottom of the needle stroke, the needle flowapertures are spaced below the bottom wall of the stopper and adjacentor contiguous thereto (i.e., the upstream end of each hole is adjacentto the inside surface of the bottom wall of the stopper). In one suchembodiment, the needle tip penetrates beyond the inside surface of thebottom wall of the stopper to a depth within the range of about 1 toabout 5 cm, preferably within the range of about 1 to about 3 cm, andmost preferably about 1.5 centimeters. At the bottom of the needlestroke, the medicament or other substance is delivered therethrough andinto the vials. Then, when the predetermined amount of medicament orother substance is delivered, the needles are withdrawn. Preferably, theneedle and/or stopper is treated to reduce friction at least at theneedle/stopper interface to, in turn, further prevent the formation ofparticles. In the latter embodiment, the needles are not withdrawn whilefilling. Rather, the needles penetrate the stoppers a minimum amount asindicated above to allow filling while holding the needles in place, forexample, at the bottom of the stroke, and then the needles are withdrawnfrom the stoppers after filling. One advantage of this embodiment isthat it reduces the relative movement of the needle and stoppersurfaces, and thus facilitates in preventing the formation of particlesduring needle penetration and withdrawal.

Also during the dwell, the four laser optic assemblies 2232-2238 deliverlaser energy to the resealable stoppers on the four containers beneaththe laser and IR manifold to reseal said stoppers. As the resealablestoppers are heated by the laser energy, the four IR sensors 2242-2248detect the temperature of each stopper, so as to be able to determinewhether each stopper was heated sufficient to cause resealing. After thedwell, the process is repeated, i.e., four star wheels 2152, 2154, 2156,2158 index another four positions and then dwell again so that the nextfour containers are filled and four more containers are resealed.

After resealing, the containers are transferred to the third star wheel2156, which employs the vacuum ports in its recesses to retain eachcontainer as it is transported. If a container was successfully filledand sealed, then the third star wheel 2156 transports that containeruntil reaching the guide 2178, at which point the vacuum to theassociated vacuum port is selectively removed and the container istransferred to the guide 2178. The guide 2178 transports the containerto a bin (not shown) of successfully filled and sealed containers.

If a container was not successfully filled and sealed, then the thirdstar wheel 2156 transports that container until the container reachesthe fourth star wheel 2158, at which point the vacuum to the associatedvacuum port is selectively removed and vacuum is applied to therespective vacuum port on the fourth star wheel 2158, therebytransferring the container to the fourth star wheel 2158. The fourthstar wheel 2158 transports that container until reaching the guide 2180,at which point the vacuum to the associated vacuum port is selectivelyremoved and the container is transferred to the guide 2180, whichtransports the container to a bin of containers (not shown) that werenot successfully filled and resealed.

The turntable 2150 and four wheels 2152, 2154, 2156, 2158 are eachdriven by a respective drive shaft. Each of the drive shafts is housedwithin a shaft housing, e.g., the drive shaft for the second star wheelis housed within a shaft housing 2270. Each shaft housing includes astand, e.g., stand 2272, secured to the plate 2040 of the fill unit2014, an elongated member, e.g., member 2274, secured to the stand, anda wheel mounting member, e.g., 2276, between the elongated member andthe respective star wheel. Note that the housings are preferablyprovided with O-ring shaped seals in order to reduce the possibilitythat dirt, grease or other contaminants will enter the filling station2014 from within the housing. In this embodiment, the O-ring sealscomprise an elastic material, for example, a rubber compound such asViton.

The drive shaft of the turntable 2150 is operatively coupled to anddriven by a first drive assembly 2300 (FIG. 30B). The drive shafts ofthe star wheels are operatively coupled to and driven by a second driveassembly 2302 (FIG. 30B). In particular, the drive assembly 2302 iscoupled to a gear 2304 coupled to the drive shaft of the second starwheel 2154. The drive shafts for the first and third star wheels 2152and 2156, respectively, are driven in rotary fashion from the gear 2304for the second star wheel. The drive shaft for the fourth star wheel2156 is driven from the gear for the third star wheel 2154. Oneadvantage of this arrangement is that it results in less stack uptolerance than that achieved by a linear drive arrangement.

In this embodiment, the vertically-extending space between thecomponents of the fill assembly (e.g., the star wheels) and the plate2040 helps allow laminar, filtered airflow around these components.

In some embodiments, the needles may have grooves on the outside toallow venting of gas out of the vial upon filling. In some otherembodiments, the needles may instead be double lumen type needles, toallow venting.

The needle may have any shape now known or later discovered. In someembodiments, the needle has a tip with a pencil point shape. In someother embodiments, the needle has a tip with an arrow head shape or atrocar profile shape. In some embodiments, the shape of the needleand/or the needle tip may be adapted to help minimize or prevent theformation of particles (or debris) upon piercing the stopper, minimizewear on the needle, and/or help ensure that the stopper remainsresealable. The width of the needle may impact the fill rate. In someembodiments, the shape of the needle represents a compromise between twoor more of the above factors. In some embodiments, the amount of forceemployed to plunge the needles through the stopper is about two poundsper needle.

As shown in FIGS. 34 and 35, a typical needle 2202 defines aconically-pointed, non-coring tip (i.e., a “pencil point” tip) 2203,wherein the included angle “A” of the tip in cross-section is within therange of about 15° to about 25°, preferably about 18° to about 22°, andmost preferably about 20°. The smooth, sharply-pointed, graduallyincreasing angle of the needle tip allows for a relative smooth, andgradual expansion of the needle hole upon penetrating the stopper. Theneedle tip further defines two axially oblong flow apertures 2205 onopposite sides of the needle relative to each other. In the currentlypreferred embodiment, the needle is about 15 gage (i.e., 0.072 inchdiameter). However, as may be recognized by those of ordinary skill inthe pertinent art based on the teachings herein, this dimension is onlyexemplary and may be changed as desired or otherwise required by anapplication.

With reference to FIG. 31A and FIGS. 34 and 35, a bushing 2207 ismounted on the shank of each needle for mounting same to the needlemanifold 2200. As shown in FIG. 31A, the needle manifold includes a base2209 defining a plurality of needle mounts 2211 extending laterallytherefrom and spaced relative to each other. A needle clamp 2213 isaligned on the base 2209 by alignment pins and corresponding alignmentsapertures, and is releasably connectable to the base 2209 by screws orlike fasteners to fixedly secure the needles to the mounts. A pluralityof flow apertures 2215 extend between the needle mounts to allow laminarflow over the needles and downwardly over the vials during needlefilling. As shown typically in FIG. 31B, the needle manifold 2200 isreleasably connectable by thumb screws 2201 to a drive plate 2203 thatis, in turn, fixedly mounted to the drive shafts 2220. One advantage ofthis configuration is that the needle manifold (and associated fillinglines) can be easily replaced without tools between fills or otherwiseas required by simply turning the thumb screws.

In many embodiments, heat is generated by plunging the needles into, andextracting the needles from, the resealable caps or stoppers. In someembodiments, the medicament (or other fluid) supplied to the needlesconducts heat away from the needles and thereby helps to keep theneedles within a desired operating temperature range. In some of theseembodiments, the medicament is cooled prior to supplying the medicament(or other fluid) to the needles. In some of these embodiments, thefilling station maintains the medicament at about a predeterminedtemperature, below about a predetermined temperature, or about within apredetermined temperature range.

In some embodiments, the operation of the second arm 2115 is drivenautomatically. In some of such embodiments, the drive to the second armmay be controlled, for example, based on signals from sensors that maybe employed to detect when all of the containers have been moved off ofthe tray. In some others of such embodiments, the second arm may becontrolled for example, by a switch, actuated by an operator.

Although shown having four needles, four laser optic assemblies and fourIR sensors, it should be understood that the filling station is notlimited to such and may instead include some other number of needles,laser optic assemblies and IR sensors. It should also be understood thatthere is no absolute requirement that there be the identical numbers ofneedles, laser optic assemblies and IR sensors.

Thus, the filling machine may include any desired number of needles, ormay be mounted or driven in any of numerous different ways that arecurrently, or later become known, for performing the functions of theneedle filling station described herein. Moreover, the filling machine2010 may include a plurality of needle filling stations mounted therein,in order to increase or otherwise adjust the overall throughput of thefilling machine.

Although the needles are shown mounted on a single manifold, it shouldbe understood that this is not required. For example, in someembodiments, each needle may be individually actuatable into and out ofengagement with the resealable stoppers of the vials or othercontainers.

The drive source may take the form of any of numerous different types ofdrive sources that are currently, or later become known, for performingthe function of the drive source as described herein, such as apneumatic drive, or a solenoid-actuated or other type of electric drive.

In addition, it should be recognized that the infeed unit may take theform of any of numerous devices that are currently, or later becomeknown for performing the functions of the infeed unit, such as any ofnumerous different types of vibratory feed drives, or “pick and place”robotic systems.

Further, the transport system is not limited to turntables and starwheels. Indeed the transport system may take the form of any of numerousdifferent types of transport or conveyer systems that are currently, orlater become known, for performing the functions of the turntable and/orstar wheels described herein. For example, a transport system may takethe form of a vibratory feed drive, or may take the form of an endlessconveyor belt including, for example, a plurality of receptacles, suchas cleats, for receiving or otherwise holding the vials at predeterminedpositions on the conveyor. The transport system may be drivinglyconnected to a motor or other suitable drive source, which is controlledby a computer or other control unit to start, stop, control the speed,and otherwise coordinate operation of the transport system with theother components of the filling machine.

Further, the rejection and discharge units need not have the forms ofstar wheels but rather may have the form of pick and place robots, orany of numerous other devices that are currently or later become knownfor performing the functions of these units described herein.

It should be understood that the filling station of the presentinvention is not limited to the type of barrier system described above.For example, some filling stations use a barrier that provides anairtight seal around the filling station rather than vents to theoutside. Some of these embodiments may nonetheless provide filteredairflow, with or without laminar flow characteristics, within thefilling station. In some situations, the filling station may not need abarrier at all, but rather may be able to rely on the cleanliness of thearea in which such filling machine is located.

In some embodiments, the filling machine 2010 also includes means forvisually inspecting the filling station. This may take the form of abeta-barrier window, and/or a CCD, video or other camera mounted withinthe housing for transmitting to an external monitor images of thefilling station. As may be recognized by those skilled in the pertinentart based on the teachings herein, these particular devices are onlyexemplary, and any of numerous other devices that are currently, orlater become known, for performing the function of permitting visualinspection equally may be employed. In some embodiments, a vision systemis used to inspect each laser seal. The filling station may also beequipped with a level detection system for detecting the level of fluidor other substance within each vial or other container to ensure that itis filled to the correct level, and a labeling station.

In some embodiments, once loaded onto the filling machine 2010, thevials or other containers (or at least the needle penetration surfacesthereof) are sterilized again by laser radiation as described above, orby e-beam radiation, in order to further ensure absolute sterility ofthe requisite surfaces prior to filling and sealing. For example, insome embodiments, the filling machine may further include an e-beamassembly comprising an e-beam source as disclosed in co-pending U.S.patent application Ser. No. 10/600,525, filed Jun. 19, 2003, orco-pending international PCT Patent Application No. PCT/US03/19656,filed Jun. 19, 2003, each of which is entitled “STERILE FILLING MACHINEHAVING NEEDLE FILLING STATION WITHIN E-BEAM CHAMBER” and is herebyexpressly incorporated by reference as part of the present disclosure.

As described in these co-pending patent applications, the e-beam sourcemay be any of numerous different types of e-beam sources that arecurrently, or later become known, for performing the function of thee-beam source described herein. E-beam radiation is a form of ionizingenergy that is generally characterized by its low penetration and highdose rates. The electrons alter various chemical and molecular bondsupon contact with an exposed product, including the reproductive cellsof microorganisms, and therefore e-beam radiation is particularlysuitable for sterilizing vials, syringes and other containers formedicaments or other sterile substances. An e-beam source produces anelectron beam that is formed by a concentrated, highly charged stream ofelectrons generated by the acceleration and conversion of electricity.Preferably, the electron beam is focused onto a penetrable surface ofeach container for piercing by a needle to thereby fill the containerwith a medicament or other substance. For example, in the case of vials,such as the vials including resealable stoppers as described above, theelectron beam is focused onto the upper surface of the stopper tosterilize the penetrable surface of the stopper prior to insertion ofthe filling needle therethrough. In addition, reflective surfaces may bemounted on opposite sides of the conveyor relative to each other toreflect the e-beam, and/or the reflected and scattered electrons, ontothe sides of the vials to sterilize these surfaces of the vial.Alternatively, or in combination with such reflective surfaces, morethan one e-beam source may be employed, wherein each e-beam source isfocused onto a respective surface or surface portion of the vials orother containers to ensure sterilization of each surface area ofinterest.

In some embodiments the current, scan width, position and energy of thee-beam, the speed of the transport system, and/or the orientation andposition of any reflective surfaces, are selected to achieve at leastabout a 3 log reduction, and preferably about a 6 log reduction inbio-burden testing on the upper surface of the vial's resealablestopper, i.e., the surface of the stopper defining the penetrable regionthat is pierced by a filling needle to fill the vial. In addition, as anadded measure of caution, one or more of the foregoing variables alsoare preferably selected to achieve at least about a 3 log reduction onthe sides of the vial, i.e., on the surfaces of the vial that are notpierced by the needle during filling. These specific levels of sterilityare only exemplary, however, and the sterility levels may be set asdesired or otherwise required to validate a particular product under,for example, United States FDA or applicable European standards, such asthe applicable Sterility Assurance Levels (“SAL”). An exemplary sterilefilling machine including an e-beam unit which is adapted to needle fillwithin the e-beam chamber is described in the above-mentioned co-pendingpatent application. Further, as may be recognized by those of ordinaryskill in the pertinent art based on the teachings herein, such an e-beamunit equally may be used in connection with the sterile filling machine2010 in order to apply e-beam radiation to at least the needlepenetration regions of the stoppers, to the needles during for filling,and/or to the vials or needle penetrated regions of the vials in thelaser sealing station.

Except where otherwise stated, terms such as, for example, “comprises”,“has”, “includes”, and all forms thereof, are considered open-ended, soas not to preclude additional elements and/or features.

As may be recognized by those skilled in the pertinent art based on theteachings herein, numerous changes and modifications may be made to theabove-described and other embodiments of the present invention withoutdeparting from its scope as defined in the appended claims. For example,the resealable member may be integrally molded with the base such as byinsert molding, the resealable member may be fused or otherwise meltedto the base of the stopper, or the resealable member may be sequentiallymolded to the base. In addition, the resealable member may be made ofany of numerous different materials which are currently known, or whichlater become known for performing the functions of the resealable memberdescribed herein, such as any of numerous different thermoplastic and/orelastomeric materials, including, for example, low-density polyethylene.Similarly, the base of the stopper can be made of vulcanized rubber asdescribed above, or any of numerous other materials which are currently,or later become known as being compatible with, or otherwise defining astable enclosure for the particular medicament or other substancecontained within the vial or other container. In addition, theresealable stoppers may include more than one layer of vulcanized rubberand/or more than one layer of resealable material. In addition, thecauterization and sealing stations may employ any of numerous differenttypes of heat sources that are currently, or later become known, forperforming the functions of the heat sources described herein, such asany of numerous different types of laser or other optical sources orconductive heat sources. Accordingly, this detailed description of thepreferred embodiments is to be taken in an illustrative, as opposed to alimiting sense.

1. A method of providing and filling a device with a predeterminedsubstance, comprising the following steps: providing a needle penetrableand laser resealable portion including a thermoplastic that ispierceable with a needle to form a needle aperture therethrough, and islaser resealable to hermetically seal the needle aperture by applyinglaser radiation at a predetermined wavelength and power thereto, whereinthe needle penetrable and laser resealable portion defines apredetermined wall thickness in an axial direction thereof; providingthe thermoplastic with a predetermined amount of pigment that allows theneedle penetrable and laser resealable portion to substantially absorblaser radiation at the predetermined wavelength and substantiallyprevent the passage of radiation through the predetermined wallthickness; connecting the needle penetrable and laser resealable portionto a device defining a chamber; providing a needle defining anon-coring, conically-pointed tip and at least one flow aperture locatedadjacent to the tip and connectable in fluid communication with a sourceof the predetermined substance; configuring at least one of the needlepenetrable and laser resealable portion and needle to substantiallyprevent the formation of particles released into the chamber from thethermoplastic upon penetrating same with the needle and withdrawing theneedle therefrom; penetrating the needle penetrable and laser resealableportion with the conically-pointed tip of the needle such that the flowaperture of the needle is in fluid communication with the chamber of thedevice, and substantially preventing the formation of particles releasedinto chamber from the thermoplastic during penetration by the needle;introducing the predetermined substance through the needle and into thechamber of the device, withdrawing the needle from the needle penetrableand laser resealable portion, and substantially preventing the formationof particles released into the chamber from the thermoplastic duringwithdrawal of the needle; and transmitting laser radiation at thepredetermined wavelength and power onto the needle penetrated region ofthe needle penetrable and laser resealable portion, and hermeticallysealing the needle aperture formed in the needle penetrable and laserresealable portion and the predetermined substance within the chamber.2. A method as defined in claim 1, wherein the step of configuring atleast one of the needle penetrable and laser resealable portion andneedle to substantially prevent the formation of particles released intothe chamber includes providing a thermoplastic including a styrene blockcopolymer and an olefin, and providing a lubricant at an interface ofthe needle and needle penetrable and laser resealable portion.
 3. Amethod as defined in claim 2, wherein the step of providing a lubricantincludes providing within the thermoplastic a predetermined amount oflubricant that reduces friction forces at the interface of the needleand thermoplastic.
 4. A method as defined in claim 3, wherein the stepof providing a lubricant includes providing a lubricant selected fromthe group including silicone, mineral oil and silicone oil.
 5. A methodas defined in claim 1, wherein the step of configuring at least one ofthe needle penetrable and laser resealable portion and needle tosubstantially prevent the formation of particles released into thechamber includes providing a low-friction coating on the needle.
 6. Amethod as defined in claim 5, wherein the low-friction coating isselected from the group including tungsten carbide and titanium.
 7. Amethod as defined in claim 2, further comprising providing athermoplastic including an olefin within the range of about 3% to about20% by weight, and a styrene block copolymer within the range of about80% to about 97% by weight.
 8. A method as defined in claim 1, whereinthe step of configuring at least one of the needle penetrable and laserresealable portion and needle to substantially prevent the formation ofparticles released into the chamber includes providing a thermoplasticincluding (i) a first polymeric material in an amount within the rangeof about 80% to about 97% by weight and defining a first elongation,(ii) a second polymeric material in an amount within the range of about3% to about 20% by weight and defining a second elongation that is lessthan the first elongation of the first material, and (iii) a lubricantin an amount that reduces friction forces at an interface of the needleand needle penetrable and laser resealable portion.
 9. A method asdefined in claim 1, further comprising the steps of molding the needlepenetrable and laser resealable portion and device; and prior toallowing the needle penetrable and laser resealable portion and deviceto cool to an ambient temperature, assembling the needle penetrable andlaser resealable portion and device and forming a sealed, sterilechamber therebetween.
 10. A method as defined in claim 1, furthercomprising the step of sterilizing the sealed, empty needle penetrableand laser resealable portion and device assembly prior to the step ofneedle penetrating the needle penetrable and laser resealable portion.11. A method as defined in claim 10, wherein the sterilizing step isselected from the group including (i) applying gamma radiation, (ii)applying e-beam radiation, and (iii) applying laser radiation, to thesealed, empty needle penetrable and laser resealable portion and deviceassembly.
 12. A method as defined in claim 1, wherein the step ofproviding a needle penetrable and laser resealable portion includesproviding a needle penetrable and laser resealable portion defining anunderlying portion formed of a first material compatible with thepredetermined substance and defining a substance-exposed surface exposedto the predetermined substance within the device; and a resealableportion overlying the underlying portion, the resealable portion andunderlying portion being penetrable by the needle for introducing thepredetermined substance through the needle penetrable and laserresealable portion and into the chamber.
 13. A method as defined inclaim 12, wherein the step of providing a needle penetrable and laserresealable portion further includes providing a penetrable region of theunderlying portion that is substantially infusible in response to theapplication of thermal energy from the laser source, and providing apenetrable region of the resealable portion that is fusible in responseto the application of thermal energy from the laser source to form agas-tight seal between the resealable portion and the predeterminedsubstance in the device upon removing the needle therefrom.
 14. A methodas defined in claim 1, wherein the step of introducing the predeterminedsubstance through the needle and into the chamber of the device includesintroducing the predetermined substance through a first fluid passagewayof the needle, and allowing fluid to flow out of the chamber through asecond fluid passageway upon introducing predetermined substance fromthe first fluid passageway into the chamber.
 15. A device including aneedle penetrable and laser resealable portion that is pierceable with aneedle defining a non-coring, conically-pointed tip, to form a needleaperture therethrough to fill a chamber of the device with apredetermined substance through the needle, and is laser resealable tohermetically seal the needle aperture by applying laser radiation at apredetermined wavelength and power thereto, wherein the needlepenetrable and laser resealable portion defines a predetermined wallthickness in an axial direction thereof, and includes a thermoplastic,the thermoplastic and the needle substantially prevent the formation ofparticles released into the chamber from the needle penetrable and laserresealable portion during penetration by and withdrawal of the needle,and the thermoplastic includes a predetermined amount of pigment thatallows the thermoplastic to substantially absorb laser radiation at thepredetermined wavelength, substantially prevent the passage of radiationthrough the predetermined wall thickness thereof, and hermetically seala needle aperture formed in the needle penetration region thereof in apredetermined time period.
 16. A device as defined in claim 15, whereinthe thermoplastic includes an olefin within the range of about 3% toabout 20% by weight, a styrene block copolymer within the range of about80% to about 97% by weight, and a lubricant.
 17. A device as defined inclaim 15, wherein the thermoplastic includes (i) a first polymericmaterial in an amount within the range of about 80% to about 97% byweight and defining a first elongation, (ii) a second polymeric materialin an amount within the range of about 3% to about 20% by weight anddefining a second elongation that is less than the first elongation ofthe first material, and (iii) a lubricant in an amount that reducesfriction forces at an interface of the needle and body.
 18. A device asdefined in claim 17, wherein the first material is a styrene blockcopolymer and the second material is an olefin.
 19. A device as definedin claim 15, wherein the needle penetrable and laser resealable portionincludes an underlying portion formed of a first material compatiblewith a predetermined substance and defining a substance-exposed surfaceexposed to the predetermined substance within the device; and aresealable portion overlying the underlying portion, wherein theresealable portion is penetrable by the needle for introducing thepredetermined substance through the stopper and into the device.
 20. Adevice as defined in claim 19, wherein the penetrable region of theunderlying portion is substantially infusible in response to theapplication of radiation from the laser source, and the penetrableregion of the resealable portion is fusible in response to theapplication of radiation from the laser source to form a gas-tight sealbetween the resealable portion and the predetermined substance in thedevice after removing the needle therefrom.
 21. A device as defined inclaim 15, in combination with the needle for penetrating the needlepenetrable and laser resealable portion, wherein the non-coring,conically-pointed tip defines an included angle within the range ofabout 15 degrees to about 25 degrees.
 22. A device as defined in claim15, wherein the predetermined amount of pigment is within the range ofabout 0.3% to about 0.6% by weight.
 23. A device as defined in claim 15,wherein the device is selected from the group including (i) a vial and(ii) a syringe.
 24. A device as defined in claim 15, wherein thepredetermined time period is less than approximately 2 seconds.
 25. Adevice as defined in claim 15, in combination with a filling apparatusincluding the needle defining a non-coring, conically-pointed tip.
 26. Adevice including a needle penetrable and laser resealable portion thatis pierceable with a needle to form a needle aperture therethrough tofill a chamber of the device with a predetermined substance through theneedle, and is laser resealable to hermetically seal the needle apertureby applying laser radiation at a predetermined wavelength and powerthereto, wherein the needle penetrable and laser resealable portionincludes a thermoplastic and defines a predetermined wall thickness inan axial direction thereof, and further includes first means forsubstantially preventing the formation of particles released into thechamber from the stopper upon penetrating the stopper with the needleand withdrawing the needle from the stopper, and second means forallowing the thermoplastic to substantially absorb laser radiation atthe predetermined wavelength and substantially prevent the passage ofradiation through the predetermined wall thickness thereof, andhermetically seal a needle aperture formed in the needle penetrationregion thereof in a predetermined time period.
 27. A device as definedin claim 26, wherein the first means is defined by the thermoplasticincluding a styrene block copolymer, an olefin, and a lubricant.
 28. Adevice as defined in claim 27, wherein the thermoplastic includes anolefin within the range of about 3% to about 20% by weight and a styreneblock copolymer within the range of about 80% to about 97% by weight.29. A device as defined in claim 27, wherein the first means is definedby the thermoplastic including (i) a first polymeric material in anamount within the rang of about 80% to about 97% by weight and defininga first elongation, (ii) a second polymeric material in an amount withinthe range of about 3% to about 20% by weight and defining a secondelongation that is less than the first elongation of the first material,and (iii) a lubricant in an amount that reduces friction forces at aninterface of the needle and body.
 30. A device as defined in claim 26,wherein the predetermined time period is less than approximately 2seconds.
 31. A device as defined in claim 26, in combination with afilling apparatus including a needle defining a non-coring,conically-pointed tip.